#CHROM POS ID REF ALT #Variation ClinVar Variation Id Allele Registry Id HGVS Expressions HGNC Gene Symbol Disease Mondo Id Mode of Inheritance Assertion Applied Evidence Codes Summary of interpretation PubMed Articles Expert Panel Guideline Approval Date Published Date Retracted Evidence Repo Link Probability_Path Prediction_ACMG_tapes InterVar InterVar: InterVar and Evidence CharGer_Score CharGer_Classification 12 103234177 576 C T NM_000277.2(PAH):c.1315+1G>A 576 CA251522 NM_000277.2:c.1315+1G>A, NC_000012.12:g.102840399C>T, CM000674.2:g.102840399C>T, NC_000012.11:g.103234177C>T, CM000674.1:g.103234177C>T, NC_000012.10:g.101758307C>T, NG_008690.1:g.82204G>A, NG_008690.2:g.123012G>A, NM_000277.1:c.1315+1G>A, XM_011538422.1:c.1258+1G>A, NM_001354304.1:c.1315+1G>A, NM_000277.3:c.1315+1G>A, ENST00000307000.7:c.1300+1G>A, ENST00000551114.2:n.977+1G>A, ENST00000553106.5:c.1315+1G>A, ENST00000635477.1:n.419+1G>A, ENST00000635528.1:n.830+1G>A, NM_000277.2(PAH):c.1315+1G>A PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PVS1 [MET], PP4-Moderate [MET], PM3 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PS3: abolishes PAH activity due to protein instability (PMID:17935162; PMID:3615198); PM3: (PMID:24941924); PP4_Moderate: Reported in Galician PAH deficiency population. BH4 deficiency ruled out. (PMID:23500595); PVS1: Canonical +1 splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM3, PP4_Moderate, PVS1). 23500595, 24941924, 17935162, 3615198 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-05 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251522/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234271 577 G A NM_000277.1(PAH):c.1222C>T (p.Arg408Trp) 577 CA251523 NM_000277.1:c.1222C>T, XM_011538422.1:c.1165C>T, NM_000277.2:c.1222C>T, NM_001354304.1:c.1222C>T, NM_000277.3:c.1222C>T, ENST00000307000.7:c.1207C>T, ENST00000551114.2:n.884C>T, ENST00000553106.5:c.1222C>T, ENST00000635477.1:n.326C>T, ENST00000635528.1:n.737C>T, NC_000012.12:g.102840493G>A, CM000674.2:g.102840493G>A, NC_000012.11:g.103234271G>A, CM000674.1:g.103234271G>A, NC_000012.10:g.101758401G>A, NG_008690.1:g.82110C>T, NG_008690.2:g.122918C>T, NM_000277.1(PAH):c.1222C>T (p.Arg408Trp) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PP3: ; PS3: PMID 17935162: Table 1: p.Arg408Trp 1.85% WT activity PMID 25596310: 1.3% activity of WT (Table S4) (PMID:25596310; PMID:17935162); PP4_Moderate: most common PAH mutation in cohort; exclude BH4 deficiency. (PMID:25596310; PMID:9634518); PM3_Strong: Detected with IVS12+1G>A, M1V (Pathogenic/LP) (PMID:9634518; PMID:1971147; PMID:1609797). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PS3, PP4_Moderate, PM3_Strong). 9634518, 25596310, 1971147, 1609797, 9634518, 17935162, 25596310 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251523/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288534 581 G A NM_000277.2(PAH):c.331C>T (p.Arg111Ter) 581 CA251526 NM_000277.2:c.331C>T, NC_000012.12:g.102894756G>A, CM000674.2:g.102894756G>A, NC_000012.11:g.103288534G>A, CM000674.1:g.103288534G>A, NC_000012.10:g.101812664G>A, NG_008690.1:g.27847C>T, NG_008690.2:g.68655C>T, NM_000277.1:c.331C>T, XM_011538422.1:c.331C>T, NM_001354304.1:c.331C>T, XM_017019370.2:c.331C>T, NM_000277.3:c.331C>T, ENST00000307000.7:c.316C>T, ENST00000546844.1:c.331C>T, ENST00000548928.1:n.253C>T, ENST00000549111.5:n.427C>T, ENST00000550978.6:n.315C>T, ENST00000551337.5:c.331C>T, ENST00000551988.5:n.420C>T, ENST00000553106.5:c.331C>T, NM_000277.2(PAH):c.331C>T (p.Arg111Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PP4-Moderate [MET], PVS1 [MET], PM2 [Unmet], PM3-Very Strong [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4_Moderate: Seen in multiple Chinese PKU patients. BH4 deficiency excluded. (PMID:1301187; PMID:2816939; PMID:9860305); PM3_very-strong: Detected in trans with 6 known pathogenic variants: p.R158Q; p.R241C; p.R243Q; p.E280K; p.Y356*; p.R413P (PMID:15503242, 26322415). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PP4_Moderate, PM3_very-strong). 1301187, 9860305, 2816939, 15503242, 26322415 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251526/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246653 582 C T NM_000277.1(PAH):c.782G>A (p.Arg261Gln) 582 CA251528 NM_000277.1:c.782G>A, XM_011538422.1:c.782G>A, NM_000277.2:c.782G>A, NM_001354304.1:c.782G>A, NM_000277.3:c.782G>A, ENST00000307000.7:c.767G>A, ENST00000549247.6:n.541G>A, ENST00000553106.5:c.782G>A, NC_000012.12:g.102852875C>T, CM000674.2:g.102852875C>T, NC_000012.11:g.103246653C>T, CM000674.1:g.103246653C>T, NC_000012.10:g.101770783C>T, NG_008690.1:g.69728G>A, NG_008690.2:g.110536G>A, NM_000277.1(PAH):c.782G>A (p.Arg261Gln) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM3-Very Strong [MET], PP3 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PP3: tools predict damaging; PS3: 15.5-30% activity (PMID:2014036; PMID:25596310); PM3_VeryStrong: L48S, R408W, S349P, R243X (PMID:25596310; PMID:17935162); PP4_Moderate: (PMID:25596310). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PS3, PM3_VeryStrong, PP4_Moderate). 25596310, 17935162, 25596310, 25596310, 2014036 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-13 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251528/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 12 103246681 584 G A NM_000277.1(PAH):c.754C>T (p.Arg252Trp) 584 CA251529 NM_000277.1:c.754C>T, XM_011538422.1:c.754C>T, NM_000277.2:c.754C>T, NM_001354304.1:c.754C>T, NM_000277.3:c.754C>T, ENST00000307000.7:c.739C>T, ENST00000549247.6:n.513C>T, ENST00000553106.5:c.754C>T, NC_000012.12:g.102852903G>A, CM000674.2:g.102852903G>A, NC_000012.11:g.103246681G>A, CM000674.1:g.103246681G>A, NC_000012.10:g.101770811G>A, NG_008690.1:g.69700C>T, NG_008690.2:g.110508C>T, NM_000277.1(PAH):c.754C>T (p.Arg252Trp) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PM5 [Unmet], PM3 [MET], PP3 [MET], PP4 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: gnomAD MAF: 0.00006; PP3: tools predict damaging ; PS3: 1% residual activity (PMID:25596310; PMID:17935162); PP4: Detection of codon 252arg>trp in a patient with PAH deficiency (PMID:2574153); PM3: Detected with IVS10-11G>A, R261Q, IVS12+1, R68S (all P/LP). (PMID:18299955; PMID:11524738). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4, PM3). 11524738, 18299955, 2574153, 17935162, 25596310 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-13 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251529/MONDO:0009861/006 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103310908 586 T C NM_000277.2(PAH):c.1A>G (p.Met1Val) 586 CA114360 NM_000277.2:c.1A>G, NC_000012.12:g.102917130T>C, CM000674.2:g.102917130T>C, NC_000012.11:g.103310908T>C, CM000674.1:g.103310908T>C, NC_000012.10:g.101835038T>C, NG_008690.1:g.5473A>G, NG_008690.2:g.46281A>G, NM_000277.1:c.1A>G, XM_011538422.1:c.1A>G, NM_001354304.1:c.1A>G, XM_017019370.2:c.1A>G, NM_000277.3:c.1A>G, ENST00000307000.7:c.-147A>G, ENST00000546844.1:c.1A>G, ENST00000547319.1:n.312A>G, ENST00000549111.5:n.97A>G, ENST00000551337.5:c.1A>G, ENST00000551988.5:n.90A>G, ENST00000553106.5:c.1A>G, ENST00000635500.1:n.29-4232A>G, NM_000277.2(PAH):c.1A>G (p.Met1Val) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PVS1 [Unmet], PM2 [MET], PP4-Moderate [MET], PM3 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: gnomAD MAF=0.00002; PP4_Moderate: Seen in PKU patients. BH4 disorders ruled out. (PMID:2574002); PS3: <3% (PMID:9450897). PM3: Detected in trans with known pathogenic variants. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM3, PP4_Moderate, PS3). Updated to reflect new PVS1 recommendations. 2574002, 2574002, 9450897 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-07 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA114360/MONDO:0009861/006 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260410 587 C T NM_000277.2(PAH):c.473G>A (p.Arg158Gln) 587 CA251530 NM_000277.2:c.473G>A, NM_000277.1:c.473G>A, XM_011538422.1:c.473G>A, NM_001354304.1:c.473G>A, XM_017019370.2:c.473G>A, NM_000277.3:c.473G>A, ENST00000307000.7:c.458G>A, ENST00000549111.5:n.569G>A, ENST00000551988.5:n.530+10830G>A, ENST00000553106.5:c.473G>A, NC_000012.12:g.102866632C>T, CM000674.2:g.102866632C>T, NC_000012.11:g.103260410C>T, CM000674.1:g.103260410C>T, NC_000012.10:g.101784540C>T, NG_008690.1:g.55971G>A, NG_008690.2:g.96779G>A, NM_000277.2(PAH):c.473G>A (p.Arg158Gln) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM3-Very Strong [MET], PP3 [MET], PS3 [MET], PS2 [Unmet] PAH-specific ACMG/AMP criteria applied: PS3: R158Q is associated with very low levels (0.2-1.8%) of pah enzyme activity compared to wild-type. (PMID:2014036; PMID:19036622); PP3: tools predict damaging ; PP4_Moderate: BH4 testing showed responsive in a pt, pretreatment 1065uM (PMID:23500595); PM3_VeryStrong: in trans with 4 pathogenic variants: I48S, c.1315+1G>A, P281L, R261Ter. (PMID:23500595; PMID:10479481; PMID:24368688). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PP3, PP4_Moderate, PM3_VeryStrong). 23500595, 10479481, 23500595, 24368688, 19036622, 2014036 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-05 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251530/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246708 588 G A NM_000277.2(PAH):c.727C>T (p.Arg243Ter) 588 CA220585 NM_000277.2:c.727C>T, NM_000277.1:c.727C>T, XM_011538422.1:c.727C>T, NM_001354304.1:c.727C>T, NM_000277.3:c.727C>T, ENST00000307000.7:c.712C>T, ENST00000549247.6:n.486C>T, ENST00000553106.5:c.727C>T, NC_000012.12:g.102852930G>A, CM000674.2:g.102852930G>A, NC_000012.11:g.103246708G>A, CM000674.1:g.103246708G>A, NC_000012.10:g.101770838G>A, NG_008690.1:g.69673C>T, NG_008690.2:g.110481C>T, NM_000277.2(PAH):c.727C>T (p.Arg243Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PVS1 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PVS1: nonsense variant; PS3: <1% of normal PAH activity (PMID:2014036). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PS3). 2014036 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-07 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220585/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246593 589 G A NM_000277.1(PAH):c.842C>T (p.Pro281Leu) 589 CA220589 NM_000277.1:c.842C>T, NC_000012.12:g.102852815G>A, CM000674.2:g.102852815G>A, NC_000012.11:g.103246593G>A, CM000674.1:g.103246593G>A, NC_000012.10:g.101770723G>A, NG_008690.1:g.69788C>T, NG_008690.2:g.110596C>T, XM_011538422.1:c.842C>T, NM_000277.2:c.842C>T, NM_001354304.1:c.842C>T, NM_000277.3:c.842C>T, ENST00000307000.7:c.827C>T, ENST00000549247.6:n.601C>T, ENST00000553106.5:c.842C>T, ENST00000635477.1:n.3C>T, NM_000277.1(PAH):c.842C>T (p.Pro281Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM3 [MET], PP3 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PP3: ; PS3: 2% activity in bioPKU (PAH0309) (PMID:25596310; PMID:17935162); PP4_Moderate: 2 patients with moderate or classical PKU; patients with severe PKU. BH4 deficiency ruled out. (PMID:15503242; PMID:12655553); PM3: IVS4-1G>A (P/LP) (PMID:15503242). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PS3, PP4_Moderate, PM3). 12655553, 15503242, 15503242, 17935162, 25596310 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-27 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220589/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234255 592 C G NM_000277.1(PAH):c.1238G>C (p.Arg413Pro) 592 CA229414 NM_000277.1:c.1238G>C, NC_000012.12:g.102840477C>G, CM000674.2:g.102840477C>G, NC_000012.11:g.103234255C>G, CM000674.1:g.103234255C>G, NC_000012.10:g.101758385C>G, NG_008690.1:g.82126G>C, NG_008690.2:g.122934G>C, XM_011538422.1:c.1181G>C, NM_000277.2:c.1238G>C, NM_001354304.1:c.1238G>C, NM_000277.3:c.1238G>C, ENST00000307000.7:c.1223G>C, ENST00000551114.2:n.900G>C, ENST00000553106.5:c.1238G>C, ENST00000635477.1:n.342G>C, ENST00000635528.1:n.753G>C, NM_000277.1(PAH):c.1238G>C (p.Arg413Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PS3: In vitro expression of altered protein in COS cells produces severe decrease of PAH activity (<3%); PM2: Extremely low frequency. ExAC MAF=0.00012; PP4_Moderate: Detected in PKU patients, BH4 deficiency excluded; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.895; PM3: Detected with V388M (pathogenic) in 2 patients (PMID:9860305; PMID:21307867). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM2, PP4_Moderate, PP3, PM3). 21307867, 9860305 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-05 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229414/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234252 593 T C NM_000277.1(PAH):c.1241A>G (p.Tyr414Cys) 593 CA114362 NM_000277.1:c.1241A>G, XM_011538422.1:c.1184A>G, NM_000277.2:c.1241A>G, NM_001354304.1:c.1241A>G, NM_000277.3:c.1241A>G, ENST00000307000.7:c.1226A>G, ENST00000551114.2:n.903A>G, ENST00000553106.5:c.1241A>G, ENST00000635477.1:n.345A>G, ENST00000635528.1:n.756A>G, NC_000012.12:g.102840474T>C, CM000674.2:g.102840474T>C, NC_000012.11:g.103234252T>C, CM000674.1:g.103234252T>C, NC_000012.10:g.101758382T>C, NG_008690.1:g.82129A>G, NG_008690.2:g.122937A>G, NM_000277.1(PAH):c.1241A>G (p.Tyr414Cys) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM5 [MET], PM3-Very Strong [MET], PP3 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM5: c.1240T>C likely pathogenic in ClinVar; PP3: All computational evidence supports deleterious effect. REVEL=0.982; PS3: 50% activity, 50% immunoreactivity (PMID:2044609); PM3_VeryStrong: Patient #41 p.R408W / p.Y414C, Phe 744 @dx and two homozygous individuals. Total of 9 patients with this variant (PMID:22526846; PMID:17935162; PMID:9399896; PMID:21871829; PMID:26542770); PP4_Moderate: BH4 defect excluded in all patients (PMID:22526846). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM5, PP3, PS3, PM3_VeryStrong, PP4_Moderate). 22526846, 22526846, 17935162, 9399896, 26542770, 21871829, 2044609 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-07-27 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA114362/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260442 594 C T NM_000277.1(PAH):c.442-1G>A 594 CA229550 NM_000277.1:c.442-1G>A, NC_000012.12:g.102866664C>T, CM000674.2:g.102866664C>T, NC_000012.11:g.103260442C>T, CM000674.1:g.103260442C>T, NC_000012.10:g.101784572C>T, NG_008690.1:g.55939G>A, NG_008690.2:g.96747G>A, XM_011538422.1:c.442-1G>A, NM_000277.2:c.442-1G>A, NM_001354304.1:c.442-1G>A, XM_017019370.2:c.442-1G>A, NM_000277.3:c.442-1G>A, ENST00000307000.7:c.427-1G>A, ENST00000549111.5:n.538-1G>A, ENST00000551988.5:n.530+10798G>A, ENST00000553106.5:c.442-1G>A, NM_000277.1(PAH):c.442-1G>A PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4-Moderate [MET], PM3 [Unmet], PS3 [Unmet] PAH-specific ACMG/AMP criteria applied: PM2: Not present in ExAC or 1000 genomes (PMID:9860305); PVS1: Canonical -1 splice site where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 5 is present in biologically-relevant transcript. PP4_Moderate: Reported in a mild PKU patient. BH4 deficiency assessed. (PMID:14681498). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4_Moderate). 9860305, 14681498, 14681498, 21307867, 14681498 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-05 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229550/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237555 595 G C NM_000277.2(PAH):c.1068C>G (p.Tyr356Ter) 595 CA229327 NM_000277.2:c.1068C>G, NC_000012.12:g.102843777G>C, CM000674.2:g.102843777G>C, NC_000012.11:g.103237555G>C, CM000674.1:g.103237555G>C, NC_000012.10:g.101761685G>C, NG_008690.1:g.78826C>G, NG_008690.2:g.119634C>G, NM_000277.1:c.1068C>G, XM_011538422.1:c.1011C>G, NM_001354304.1:c.1068C>G, NM_000277.3:c.1068C>G, ENST00000307000.7:c.1053C>G, ENST00000549247.6:n.827C>G, ENST00000551114.2:n.730C>G, ENST00000553106.5:c.1068C>G, ENST00000635477.1:n.172C>G, ENST00000635528.1:n.583C>G, NM_000277.2(PAH):c.1068C>G (p.Tyr356Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4-Moderate [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: ExAC MAF:0.00006.; PP4_Moderate: seen in classic and mild PKU patients. BH4 deficiency excluded.. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-07 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229327/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246621 596 C A NM_000277.1(PAH):c.814G>T (p.Gly272Ter) 596 CA251532 NM_000277.1:c.814G>T, XM_011538422.1:c.814G>T, NM_000277.2:c.814G>T, NM_001354304.1:c.814G>T, NM_000277.3:c.814G>T, ENST00000307000.7:c.799G>T, ENST00000549247.6:n.573G>T, ENST00000553106.5:c.814G>T, NC_000012.12:g.102852843C>A, CM000674.2:g.102852843C>A, NC_000012.11:g.103246621C>A, CM000674.1:g.103246621C>A, NC_000012.10:g.101770751C>A, NG_008690.1:g.69760G>T, NG_008690.2:g.110568G>T, NM_000277.1(PAH):c.814G>T (p.Gly272Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extrememly low frequency in ExAC, gnomAD (MAF= 0.00006, 0.0003093); PVS1: Nonsense variant. Predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.; PP4: G272X found on one allele of a patient with classic PKU (PMID:1975559). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4). 1975559 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251532/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237528 597 GAGA G NM_000277.2(PAH):c.1092_1094del (p.Leu365del) 597 CA229337 NM_000277.2:c.1092_1094del, NC_000012.12:g.102843753_102843755del, CM000674.2:g.102843753_102843755del, NC_000012.11:g.103237531_103237533del, CM000674.1:g.103237531_103237533del, NC_000012.10:g.101761661_101761663del, NG_008690.1:g.78850_78852del, NG_008690.2:g.119658_119660del, NM_000277.1:c.1092_1094del, XM_011538422.1:c.1035_1037del, NM_001354304.1:c.1092_1094del, NM_000277.3:c.1092_1094del, ENST00000307000.7:c.1077_1079del, ENST00000549247.6:n.851_853del, ENST00000551114.2:n.754_756del, ENST00000553106.5:c.1092_1094del, ENST00000635477.1:n.196_198del, ENST00000635528.1:n.607_609del, NM_000277.2(PAH):c.1092_1094del (p.Leu365del) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM4 [MET], PM3 [MET], PP4 [MET] The c.1092_1094delTCT variant in PAH has been previously reported as a single variant, found in trans with the Pathogenic variant (per internal PAH ClinGen Working Group classification, see ClinVar allele ID 15635) p.Gly272Ter in one proband with classic PKU (PMID: 1975559); phase was confirmed via parental testing (PM3). Apart from stating that the proband was identified via newborn screening further detail is provided regarding the proband’s phenotype, including whether BH4 deficiency was formally excluded (PP4?). The variant is a protein-length changing variant in a non-repeat region (PM4). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). 1975559, 1975559 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229337/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246617 598 G A NM_000277.2(PAH):c.818C>T (p.Ser273Phe) 598 CA229785 NM_000277.2:c.818C>T, NM_000277.1:c.818C>T, XM_011538422.1:c.818C>T, NM_001354304.1:c.818C>T, NM_000277.3:c.818C>T, ENST00000307000.7:c.803C>T, ENST00000549247.6:n.577C>T, ENST00000553106.5:c.818C>T, NC_000012.12:g.102852839G>A, CM000674.2:g.102852839G>A, NC_000012.11:g.103246617G>A, CM000674.1:g.103246617G>A, NC_000012.10:g.101770747G>A, NG_008690.1:g.69764C>T, NG_008690.2:g.110572C>T, NM_000277.2(PAH):c.818C>T (p.Ser273Phe) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC and gnomAD (1 allele); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.978; PP4_Moderate: S273F was detected in in Northern Ireland, Belgium/French, Western Scotland, and New South Wales PKU patients. BH4 deficiency was assessed in 1 study. Upgraded per ClinGen Metabolic workgroup. (PMID:1671881; PMID:8533759; PMID:9012412; PMID:24368688); PM3_Strong: Seen with 2 known pathogenic mutations: I65T, R408W. Upgraded based on SVI worgroup recommendations and approved PAH guidelines (PMID:24368688). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong). 1671881, 24368688, 9012412, 8533759, 24368688 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229785/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246592 599 C T NM_000277.2(PAH):c.842+1G>A 599 CA229811 NM_000277.2:c.842+1G>A, NM_000277.1:c.842+1G>A, XM_011538422.1:c.842+1G>A, NM_001354304.1:c.842+1G>A, NM_000277.3:c.842+1G>A, ENST00000307000.7:c.827+1G>A, ENST00000549247.6:n.601+1G>A, ENST00000553106.5:c.842+1G>A, ENST00000635477.1:n.3+1G>A, NC_000012.12:g.102852814C>T, CM000674.2:g.102852814C>T, NC_000012.11:g.103246592C>T, CM000674.1:g.103246592C>T, NC_000012.10:g.101770722C>T, NG_008690.1:g.69789G>A, NG_008690.2:g.110597G>A, NM_000277.2(PAH):c.842+1G>A PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [MET], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Canonical +1 splice site; PM2: gnomAD MAF 0.00008; PP4: Reported in 3 PKU populations: Slovak, Germany, Italy (PMID:1671810; PMID:10394930; PMID:23764561); PM3: (PMID:20188615; PMID:24941924). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4, PM3). 24941924, 20188615, 10394930, 23764561, 1671810 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-13 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229811/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237426 601 T A NM_000277.1(PAH):c.1197A>T (p.Val399=) 601 CA229379 NM_000277.1:c.1197A>T, XM_011538422.1:c.1140A>T, NM_000277.2:c.1197A>T, NM_001354304.1:c.1197A>T, NM_000277.3:c.1197A>T, ENST00000307000.7:c.1182A>T, ENST00000549247.6:n.956A>T, ENST00000551114.2:n.859A>T, ENST00000553106.5:c.1197A>T, ENST00000635477.1:n.301A>T, ENST00000635528.1:n.712A>T, NC_000012.12:g.102843648T>A, CM000674.2:g.102843648T>A, NC_000012.11:g.103237426T>A, CM000674.1:g.103237426T>A, NC_000012.10:g.101761556T>A, NG_008690.1:g.78955A>T, NG_008690.2:g.119763A>T, NM_000277.1(PAH):c.1197A>T (p.Val399=) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3 [MET], PS3 [MET] The c.1197A>T (p.Val399=) variant in PAH has been reported on 7 alleles of PKU patients (BH4 deficiency excluded). (PP4_Moderate; PMID: 23271928; PMID: 11214902). This variant has an extremely low allele frequency (0.000004064) in gnomAD (PM2; http://gnomAD.broadinstitute.org). This variant induces post-transcriptional skipping of exon 11 (PS3; PMID: 11214902). This variant was detected in trans with R408W (Pathogenic in ClinVar) (PM3; PMID: 11214902). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate 23271928, 11214902, 11214902, 11214902 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-07-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229379/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246606 603 A C NM_000277.2(PAH):c.829T>G (p.Tyr277Asp) 603 CA251534 NM_000277.2:c.829T>G, NM_000277.1:c.829T>G, XM_011538422.1:c.829T>G, NM_001354304.1:c.829T>G, NM_000277.3:c.829T>G, ENST00000307000.7:c.814T>G, ENST00000549247.6:n.588T>G, ENST00000553106.5:c.829T>G, NC_000012.12:g.102852828A>C, CM000674.2:g.102852828A>C, NC_000012.11:g.103246606A>C, CM000674.1:g.103246606A>C, NC_000012.10:g.101770736A>C, NG_008690.1:g.69775T>G, NG_008690.2:g.110583T>G, NM_000277.2(PAH):c.829T>G (p.Tyr277Asp) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3 [MET], PP3 [MET], PS3 [MET] The c.829T>G (p.Tyr277Asp) variant in PAH has been reported in 2 individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925; PMID: 23500595). This variant has an extremely low allele frequency (1/121400) in ExAC (PM2; http://exac.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with L48S (Pathogenic in ClinVar) (PM3; PMID: 23500595). Computational prediction tools and conservation analysis suggest that the c.829T>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3 23500595, 8268925, 23500595 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-05 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251534/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237568 607 C T NM_000277.1(PAH):c.1066-11G>A 607 CA251538 NM_000277.1:c.1066-11G>A, XM_011538422.1:c.1009-11G>A, NM_000277.2:c.1066-11G>A, NM_001354304.1:c.1066-11G>A, NM_000277.3:c.1066-11G>A, ENST00000307000.7:c.1051-11G>A, ENST00000549247.6:n.825-11G>A, ENST00000551114.2:n.728-11G>A, ENST00000553106.5:c.1066-11G>A, ENST00000635477.1:n.170-11G>A, ENST00000635528.1:n.581-11G>A, NC_000012.12:g.102843790C>T, CM000674.2:g.102843790C>T, NC_000012.11:g.103237568C>T, CM000674.1:g.103237568C>T, NC_000012.10:g.101761698C>T, NG_008690.1:g.78813G>A, NG_008690.2:g.119621G>A, NM_000277.1(PAH):c.1066-11G>A PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET], PM3-Strong [MET], PS3 [MET] The c.1066-11G>A variant in PAH has been reported in > 76 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 23500595; PMID: 8990013). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with multiple known pathogenic variants: p.R243Q, p.R243X, p.R261Q, p.R270K, p.I65T. (PM3_Strong; PMID: 23500595; PMID: 8990013). Computational prediction tools and conservation analysis suggest that the c.1066-11G>A variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong 8990013, 23500595, 8990013, 23500595, 1769645 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-10-01 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251538/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103306594 608 A G NM_000277.2(PAH):c.143T>C (p.Leu48Ser) 608 CA251539 NM_000277.2:c.143T>C, NM_000277.1:c.143T>C, XM_011538422.1:c.143T>C, NM_001354304.1:c.143T>C, XM_017019370.2:c.143T>C, NM_000277.3:c.143T>C, ENST00000307000.7:c.128T>C, ENST00000546844.1:c.143T>C, ENST00000548677.2:n.230T>C, ENST00000548928.1:n.65T>C, ENST00000549111.5:n.239T>C, ENST00000550978.6:n.127T>C, ENST00000551337.5:c.143T>C, ENST00000551988.5:n.232T>C, ENST00000553106.5:c.143T>C, ENST00000635500.1:n.111T>C, NC_000012.12:g.102912816A>G, CM000674.2:g.102912816A>G, NC_000012.11:g.103306594A>G, CM000674.1:g.103306594A>G, NC_000012.10:g.101830724A>G, NG_008690.1:g.9787T>C, NG_008690.2:g.50595T>C, NM_000277.2(PAH):c.143T>C (p.Leu48Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM3 [MET], PP3 [MET], PP1 [MET], PS3 [MET] The c.143T>C (p.Leu48Ser) variant in PAH has been reported multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 26322415, 16879198, 1679030). This variant has a frequency that is higher than the suggested cutoff for PM2 by the PAH VCEP (MAF=0.00026). This variant has 39% residual activity (PS3, PMID: 17935162). This variant was detected in trans with p.G247R (LP, 2 submitters) PM3, PMID: 26322415). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Cosegregation with PKU in 2 siblings for 2 unrelated families was reported ( PMID: 23430547). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3, PP1, PP3. 26322415, 1679030, 16879198, 26322415, 23430547, 17935162 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA251539/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246654 610 G A NM_000277.1(PAH):c.781C>T (p.Arg261Ter) 610 CA229757 NM_000277.1:c.781C>T, XM_011538422.1:c.781C>T, NM_000277.2:c.781C>T, NM_001354304.1:c.781C>T, NM_000277.3:c.781C>T, ENST00000307000.7:c.766C>T, ENST00000549247.6:n.540C>T, ENST00000553106.5:c.781C>T, NC_000012.12:g.102852876G>A, CM000674.2:g.102852876G>A, NC_000012.11:g.103246654G>A, CM000674.1:g.103246654G>A, NC_000012.10:g.101770784G>A, NG_008690.1:g.69727C>T, NG_008690.2:g.110535C>T, NM_000277.1(PAH):c.781C>T (p.Arg261Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PVS1 [MET], PM3 [MET], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4: Detected in 2 unrelated patients (PMID:1682234); PM3: Detected with H170D, pathogenic (PMID:11385716). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PP4, PM3). 11385716, 1682234 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-05 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229757/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103306571 611 CA C NM_000277.2(PAH):c.165delT (p.Phe55Leufs) 611 CA251540 NC_000012.12:g.102912796del, CM000674.2:g.102912796del, NC_000012.11:g.103306574del, CM000674.1:g.103306574del, NC_000012.10:g.101830704del, NG_008690.1:g.9809del, NG_008690.2:g.50617del, NM_000277.1:c.165del, XM_011538422.1:c.165del, NM_000277.2:c.165del, NM_001354304.1:c.165del, XM_017019370.2:c.165del, NM_000277.3:c.165del, ENST00000307000.7:c.150del, ENST00000546844.1:c.165del, ENST00000548677.2:n.252del, ENST00000548928.1:n.87del, ENST00000549111.5:n.261del, ENST00000550978.6:n.149del, ENST00000551337.5:c.165del, ENST00000551988.5:n.254del, ENST00000553106.5:c.165del, ENST00000635500.1:n.133del, NM_000277.2(PAH):c.165delT (p.Phe55Leufs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] The c.165delT (p.F55Lfs*6) is a frameshift variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in compound heterozygote state in multiple patients with PKU (BH4 deficiency not excluded) (PMID: 1682235 & 23500595). The variants in trans include: R408W, and R261Q, both confirmed pathogenic.This variant has an extremely low allele frequency in the Genome Aggregation database (3/251384) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria: PM2, PP4, PVS1. 1682235, 23500595 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA251540/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234270 612 C T NM_000277.1(PAH):c.1223G>A (p.Arg408Gln) 612 CA229404 NM_000277.1:c.1223G>A, NC_000012.12:g.102840492C>T, CM000674.2:g.102840492C>T, NC_000012.11:g.103234270C>T, CM000674.1:g.103234270C>T, NC_000012.10:g.101758400C>T, NG_008690.1:g.82111G>A, NG_008690.2:g.122919G>A, XM_011538422.1:c.1166G>A, NM_000277.2:c.1223G>A, NM_001354304.1:c.1223G>A, NM_000277.3:c.1223G>A, ENST00000307000.7:c.1208G>A, ENST00000551114.2:n.885G>A, ENST00000553106.5:c.1223G>A, ENST00000635477.1:n.327G>A, ENST00000635528.1:n.738G>A, NM_000277.1(PAH):c.1223G>A (p.Arg408Gln) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PP3 [MET], PS3 [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM3_Strong: In trans with R408W, IVS4-1G>A, R241C (ClinGen, P) (PMID:1312992; PMID:14722928); PP3: ; PS3: Mutant enzyme activity of 46% in BioPKU (PMID:9860305); PP4_Moderate: ~830 uml/L w/o BH4 deficiency & 823 umol/L, BH4 status unknown (PMID:9860305; PMID:1312992). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM3_Strong, PP3, PS3, PP4_Moderate). 1312992, 9860305, 9860305, 1312992, 14722928 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-05 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229404/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234250 617 C T NM_000277.1(PAH):c.1243G>A (p.Asp415Asn) 617 CA114364 NM_000277.1:c.1243G>A, NC_000012.12:g.102840472C>T, CM000674.2:g.102840472C>T, NC_000012.11:g.103234250C>T, CM000674.1:g.103234250C>T, NC_000012.10:g.101758380C>T, NG_008690.1:g.82131G>A, NG_008690.2:g.122939G>A, XM_011538422.1:c.1186G>A, NM_000277.2:c.1243G>A, NM_001354304.1:c.1243G>A, NM_000277.3:c.1243G>A, ENST00000307000.7:c.1228G>A, ENST00000551114.2:n.905G>A, ENST00000553106.5:c.1243G>A, ENST00000635477.1:n.347G>A, ENST00000635528.1:n.758G>A, NM_000277.1(PAH):c.1243G>A (p.Asp415Asn) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3-Very Strong [MET], PP3 [Unmet], PS3 [Unmet] The c.1243G>A (p.Asp415Asn) variant in PAH has been reported in 3 patients with Hyperphenylalaninemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 1358789). This variant has an extremely low allele frequency (0.0001097 in gnomAD) (PM2; http://gnomad.broadinstitute.org). This variant was detected in trans with R408W, F39L, Y414C, IVS10-11G>A (Pathogenic in ClinVar) (PM3_Very-strong; PMID: 1358789; PMID: 12501224; PMID: 18299955). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong 1358789, 1358789, 12501224, 18299955, 11161839 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-12 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA114364/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103240726 618 T C NM_000277.1(PAH):c.916A>G (p.Ile306Val) 618 CA114365 NM_000277.1:c.916A>G, XM_011538422.1:c.913-2517A>G, NM_000277.2:c.916A>G, NM_001354304.1:c.916A>G, NM_000277.3:c.916A>G, ENST00000307000.7:c.901A>G, ENST00000549247.6:n.675A>G, ENST00000551114.2:n.578A>G, ENST00000553106.5:c.916A>G, ENST00000635477.1:n.74-2517A>G, ENST00000635528.1:n.431A>G, NC_000012.12:g.102846948T>C, CM000674.2:g.102846948T>C, NC_000012.11:g.103240726T>C, CM000674.1:g.103240726T>C, NC_000012.10:g.101764856T>C, NG_008690.1:g.75655A>G, NG_008690.2:g.116463A>G, NM_000277.1(PAH):c.916A>G (p.Ile306Val) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3 [MET], PP3 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: MAF = 2.0e-5; PP3: Software agrees on a damaging effect.; PS3: Mutation ID#1, 18% residual enzyme activity (PMID:18590700); PM3: I306V / F55L (pathogenic in ClinVar) in a single patient with mild HPA (PMID:18299955); PP4_Moderate: BH4 defect excluded in all patients--single patient with mild hyperphe (Bercovich, 2008). (PMID:18299955). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate). 18299955, 18299955, 18590700 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA114365/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237461 619 C T NM_000277.1(PAH):c.1162G>A (p.Val388Met) 619 CA251543 NM_000277.1:c.1162G>A, XM_011538422.1:c.1105G>A, NM_000277.2:c.1162G>A, NM_001354304.1:c.1162G>A, NM_000277.3:c.1162G>A, ENST00000307000.7:c.1147G>A, ENST00000549247.6:n.921G>A, ENST00000551114.2:n.824G>A, ENST00000553106.5:c.1162G>A, ENST00000635477.1:n.266G>A, ENST00000635528.1:n.677G>A, NC_000012.12:g.102843683C>T, CM000674.2:g.102843683C>T, NC_000012.11:g.103237461C>T, CM000674.1:g.103237461C>T, NC_000012.10:g.101761591C>T, NG_008690.1:g.78920G>A, NG_008690.2:g.119728G>A, NM_000277.1(PAH):c.1162G>A (p.Val388Met) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PM3 [MET], PP3 [MET], PP4 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low in ExAC and 1000 genomes (PMID:9860305); PS3: PAH activity in COS cell expression system 15% (PMID:9860305); PM3: Compound het with severe mutation (PMID:9860305); PP3: ; PP4: Reported in patient with classic PKU (PMID:9860305). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PS3, PM3, PP3, PP4). 9860305, 9860305, 9860305, 9860305 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-05 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251543/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103237454 625 T C NM_000277.1(PAH):c.1169A>G (p.Glu390Gly) 625 CA114367 NM_000277.1:c.1169A>G, NC_000012.12:g.102843676T>C, CM000674.2:g.102843676T>C, NC_000012.11:g.103237454T>C, CM000674.1:g.103237454T>C, NC_000012.10:g.101761584T>C, NG_008690.1:g.78927A>G, NG_008690.2:g.119735A>G, XM_011538422.1:c.1112A>G, NM_000277.2:c.1169A>G, NM_001354304.1:c.1169A>G, NM_000277.3:c.1169A>G, ENST00000307000.7:c.1154A>G, ENST00000549247.6:n.928A>G, ENST00000551114.2:n.831A>G, ENST00000553106.5:c.1169A>G, ENST00000635477.1:n.273A>G, ENST00000635528.1:n.684A>G, NM_000277.1(PAH):c.1169A>G (p.Glu390Gly) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM3-Very Strong [MET], PP3 [MET], PS3 [Unmet] The c.1169A>G (p.Glu390Gly) variant in PAH has been reported on at least 47 alleles, most often with Mild Hyperphenylalaninemia. (BH4 deficiency excluded). (PP4_Moderate; PMID: 8088845; PMID: 21147011). This variant has an extremely low allele frequency (MAF=0.00018 in gnomAD) (PM2; http://gnomAD.broadinstitute.org). This variant was detected in trans with IVS-12nt1, L333F (Pathogenic in ClinVar) + 8 homozygotes (PM3_Very-strong; PMID: 10479481; PMID: 21147011; PMID: 8088845). Computational prediction tools and conservation analysis suggest that the c.1169A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong 21147011, 8088845, 21147011, 8088845, 10479481, 21147011, 10479481 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-10-01 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA114367/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103288572 627 A G NM_000277.2(PAH):c.293T>C (p.Leu98Ser) 627 CA114368 NM_000277.2:c.293T>C, NM_000277.1:c.293T>C, XM_011538422.1:c.293T>C, NM_001354304.1:c.293T>C, XM_017019370.2:c.293T>C, NM_000277.3:c.293T>C, ENST00000307000.7:c.278T>C, ENST00000546844.1:c.293T>C, ENST00000548928.1:n.215T>C, ENST00000549111.5:n.389T>C, ENST00000550978.6:n.277T>C, ENST00000551337.5:c.293T>C, ENST00000551988.5:n.382T>C, ENST00000553106.5:c.293T>C, NC_000012.12:g.102894794A>G, CM000674.2:g.102894794A>G, NC_000012.11:g.103288572A>G, CM000674.1:g.103288572A>G, NC_000012.10:g.101812702A>G, NG_008690.1:g.27809T>C, NG_008690.2:g.68617T>C, NM_000277.2(PAH):c.293T>C (p.Leu98Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PP3 [MET] The c.293T>C (p.Leu98Ser) variant in PAH has been reported in a Pakistani patient with non-PKU hyperphenylalaninemia (BH4 deficiency excluded) (PP4_Moderate; PMID: 8364546, 9634518) This variant is absent from 1000G and ESP, and has an extremely low frequency in ExAC and gnomAD (MAF=0.00016). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.846. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. 8364546, 9634518 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA114368/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237484 628 G A NM_000277.1(PAH):c.1139C>T (p.Thr380Met) 628 CA114369 NM_000277.1:c.1139C>T, XM_011538422.1:c.1082C>T, NM_000277.2:c.1139C>T, NM_001354304.1:c.1139C>T, NM_000277.3:c.1139C>T, ENST00000307000.7:c.1124C>T, ENST00000549247.6:n.898C>T, ENST00000551114.2:n.801C>T, ENST00000553106.5:c.1139C>T, ENST00000635477.1:n.243C>T, ENST00000635528.1:n.654C>T, NC_000012.12:g.102843706G>A, CM000674.2:g.102843706G>A, NC_000012.11:g.103237484G>A, CM000674.1:g.103237484G>A, NC_000012.10:g.101761614G>A, NG_008690.1:g.78897C>T, NG_008690.2:g.119705C>T, NM_000277.1(PAH):c.1139C>T (p.Thr380Met) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM5 [Unmet], PM3-Very Strong [MET], PP3 [MET], PS3 [MET] The c.1139C>T (p.Thr380Met) variant in PAH has been reported in 1 patient with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925). This variant has 28% enzyme activity (PS3; PMID: 27620137). This variant was detected in trans with multiple known pathogenic variants: R408W, R261Q, I65T, F299C (PM3_Very-strong; PMID: 7981714). Computational prediction tools and conservation analysis suggest that the c.1139C>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Very-strong 8268925, 7981714, 27620137 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-10-01 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA114369/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246701 632 A G NM_000277.2(PAH):c.734T>C (p.Val245Ala) 632 CA114372 NM_000277.2:c.734T>C, NM_000277.1:c.734T>C, XM_011538422.1:c.734T>C, NM_001354304.1:c.734T>C, NM_000277.3:c.734T>C, ENST00000307000.7:c.719T>C, ENST00000549247.6:n.493T>C, ENST00000553106.5:c.734T>C, NC_000012.12:g.102852923A>G, CM000674.2:g.102852923A>G, NC_000012.11:g.103246701A>G, CM000674.1:g.103246701A>G, NC_000012.10:g.101770831A>G, NG_008690.1:g.69680T>C, NG_008690.2:g.110488T>C, NM_000277.2(PAH):c.734T>C (p.Val245Ala) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM5 [MET], PM3-Very Strong [MET], PP3 [Unmet], PS3 [Unmet] PAH-specific ACMG/AMP criteria applied: PM5: V245L Pathogenic; PP4_Moderate: Seen in at least 7 MHP patients. Exclusion of a defect in tetrahydrobiopterin metabolism. Upgraded per ClinGen Metabolic Workgroup. (PMID:7981714; PMID:9298832; PMID:9634518); PM3_VeryStrong: V245A detected with IVS-12nt1, R252W, L194P (both P/LP), R408W (Path). Upgraded per ClinGen SVI Workgroup (PMID:7981714; PMID:9298832; PMID:8088845). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM5, PP4_Moderate, PM3_VeryStrong). 9298832, 9634518, 7981714, 8088845, 9298832, 7981714, 11161839 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA114372/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103238111 633 T C NM_000277.2(PAH):c.1065+3A>G 633 CA212751 NM_000277.2:c.1065+3A>G, NM_000277.1:c.1065+3A>G, XM_011538422.1:c.1008+3A>G, NM_001354304.1:c.1065+3A>G, NM_000277.3:c.1065+3A>G, ENST00000307000.7:c.1050+3A>G, ENST00000549247.6:n.824+3A>G, ENST00000551114.2:n.727+3A>G, ENST00000553106.5:c.1065+3A>G, ENST00000635477.1:n.169+3A>G, ENST00000635528.1:n.580+3A>G, NC_000012.12:g.102844333T>C, CM000674.2:g.102844333T>C, NC_000012.11:g.103238111T>C, CM000674.1:g.103238111T>C, NC_000012.10:g.101762241T>C, NG_008690.1:g.78270A>G, NG_008690.2:g.119078A>G, NM_000277.2(PAH):c.1065+3A>G PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM3 [MET], PP3 [MET], PP4 [MET], PP1 [MET] The c.1065+3A>G variant in PAH was detected in 2 siblings with an increased serum Phenylalanine level of 365 uM. BH4 deficiency was not assessed/reported. (PMID: 8088845) They were compound heterozygous for Y414C. The c.1065+3A>G variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted for this variant in HSF and MaxEnt (Alteration of the WT donor site; activation of an intronic cryptic donor site). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP1, PP3, PP4. 8088845, 8088845, 8088845 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA212751/MONDO:0009861/006 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288671 636 A G NM_000277.2(PAH):c.194T>C (p.Ile65Thr) 636 CA251544 NM_000277.2:c.194T>C, NC_000012.12:g.102894893A>G, CM000674.2:g.102894893A>G, NC_000012.11:g.103288671A>G, CM000674.1:g.103288671A>G, NC_000012.10:g.101812801A>G, NG_008690.1:g.27710T>C, NG_008690.2:g.68518T>C, NM_000277.1:c.194T>C, XM_011538422.1:c.194T>C, NM_001354304.1:c.194T>C, XM_017019370.2:c.194T>C, NM_000277.3:c.194T>C, ENST00000307000.7:c.179T>C, ENST00000546844.1:c.194T>C, ENST00000548677.2:n.281T>C, ENST00000548928.1:n.116T>C, ENST00000549111.5:n.290T>C, ENST00000550978.6:n.178T>C, ENST00000551337.5:c.194T>C, ENST00000551988.5:n.283T>C, ENST00000553106.5:c.194T>C, ENST00000635500.1:n.162T>C, NM_000277.2(PAH):c.194T>C (p.Ile65Thr) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM5 [Unmet], PM3-Very Strong [MET], PP3 [MET], PP1 [Unmet], PS1 [Unmet], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM3_VeryStrong: Detected with Y414C (P), R408W (P), P281L (P), IVS10nt-11 (P), R252W (P/LP), and R243Q(P). (PMID:12501224; PMID:1301201; PMID:10767174); PP3: Predicted dleterious in SIZFT, Polyphen2, MutationTaster. REVEL=0.985; PP4_Moderate: Detected in a patient with mild PKU. BH4 deficiency excluded. Upgraded per ClinGen PAH EP. (PMID:12501224); PS3: 25% mutant enzyme activity in COS cells as compared in wt (PMID:1301201). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM3_VeryStrong, PP3, PP4_Moderate, PS3). 21871829, 12501224, 10767174, 1301201, 12501224, 1301201 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-04-21 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA251544/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 1 216363621 2353 CAG C NM_007123.5(USH2A):c.4338_4339delCT (p.Cys1447Glnfs) 2353 CA252228 NM_007123.5:c.4338_4339delCT, NC_000001.11:g.216190284_216190285del, CM000663.2:g.216190284_216190285del, NC_000001.10:g.216363626_216363627del, CM000663.1:g.216363626_216363627del, NC_000001.9:g.214430249_214430250del, NG_009497.1:g.238116_238117del, NM_007123.5:c.4338_4339del, NM_206933.2:c.4338_4339del, NM_206933.3:c.4338_4339del, ENST00000307340.7:c.4338_4339del, ENST00000366942.3:c.4338_4339del, NM_007123.5(USH2A):c.4338_4339delCT (p.Cys1447Glnfs) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Pathogenic PP1-Moderate [MET], PM2 [MET], PVS1 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP4 [MET], PM3-Very Strong [MET], BA1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] The allele frequency of the p.Cys1447GlnfsX29 variant in the USH2A gene is 0.0009% (1/111250) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The p.Cys1447GlnfsX29 variant is predicted to cause a premature stop codon in biologically-relevant-exon 20 of 72 that leads to an absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected as compound heterozygous with p.Cys759Phe or p.Glu767SerfsX21 in six Usher syndrome probands, and as homozygous in eight Usher syndrome probands (PM3_VeryStrong; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). The p.Cys1447GlnfsX29 variant in USH2A has been reported to segregate with hearing loss in at least 2 family members (PP1_Moderate; PMID: 20440071, 9624053). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PVS1, PM3_VeryStrong, PP1_Moderate, PP4. 20440071, 9624053, 20440071, 18641288, 15325563, 9624053, 18665195, 20440071, 15325563, 18641288, 9624053, 18665195, 20440071, 15325563, 18641288, 9624053, 18665195, 20613545, 10729113, 20440071, 9624053 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-25 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA252228/MONDO:0019501/005 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 7 107301201 4838 T C NM_000441.1(SLC26A4):c.-103T>C 4838 CA253314 NM_000441.1:c.-103T>C, NR_028137.1:n.198-550A>G, ENST00000265715.7:c.-103T>C, NC_000007.14:g.107660756T>C, CM000669.2:g.107660756T>C, NC_000007.13:g.107301201T>C, CM000669.1:g.107301201T>C, NC_000007.12:g.107088437T>C, NG_008489.1:g.5122T>C, NM_000441.1(SLC26A4):c.-103T>C SLC26A4-AS1 Pendred syndrome MONDO:0010134 Autosomal recessive inheritance Uncertain Significance PS3-Supporting [MET], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [MET], BS2 [Unmet], BS1-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS2 [Unmet], PS4 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], PM3 [MET], BP5 [Unmet], BP7 [Unmet], BS4 [Unmet] The filtering allele frequency of the c.-103T>C variant in the SLC26A4 gene is 0.28% for European (Non-Finnish) chromosomes by the Genome Aggregation Database (53/14998 with 95% CI), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been detected one patient with EVA in trans with p.Leu236Pro, pathogenic variant, as well as in two patients with EVA in which the variant in trans is benign (c.-66C>G) or the phase was not identified (p.Thr416Pro) (PM3; PMID:19204907, 30068397, 25991456). The variant has also been observed in 12 heterozygous cases in which a second variant was not identified (PMID: 17503324, 29196752, 25991456, 23208854). At least one patient with a variant in this gene displayed features of enlarged vestibular aqueduct (PP4; PMID: 19204907). Functional studies demonstrate that this variant may impact FOXI1-induced transcriptional activation of SLC26A4 (PS3_Supporting; PMID: 17503324, 25910213). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, PM3, PP4, PS3_Supporting. 25910213, 17503324, 19204907, 29196752, 30068397, 25991456, 23208854, 17503324, 23965030, 19204907, 29196752, 30068397, 25991456, 23208854, 17503324, 23965030 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA253314/MONDO:0010134/005 0.0507 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 73572579 4926 C T NM_022124.5(CDH23):c.9565C>T (p.Arg3189Trp) 4926 CA117145 NM_022124.5:c.9565C>T, NC_000010.11:g.71812822C>T, CM000672.2:g.71812822C>T, NC_000010.10:g.73572579C>T, CM000672.1:g.73572579C>T, NC_000010.9:g.73242585C>T, NG_008835.1:g.420876C>T, NM_001171933.1:c.2845C>T, NM_001171934.1:c.2845C>T, NM_001171935.1:c.256C>T, NM_001171936.1:c.256C>T, XM_006717940.2:c.9760C>T, XM_006717942.2:c.9694C>T, XM_011540039.1:c.9757C>T, XM_011540040.1:c.9754C>T, XM_011540041.1:c.9700C>T, XM_011540042.1:c.9670C>T, XM_011540043.1:c.9760C>T, XM_011540044.1:c.9625C>T, XM_011540045.1:c.9760C>T, XM_011540046.1:c.9220C>T, XM_011540047.1:c.8578C>T, XM_011540052.1:c.6088C>T, ENST00000224721.10:c.9580C>T, ENST00000398788.4:c.2845C>T, ENST00000475158.1:n.3101C>T, ENST00000619887.4:c.2845C>T, ENST00000622827.4:c.9565C>T, NM_022124.5(CDH23):c.9565C>T (p.Arg3189Trp) CDH23 Usher syndrome type 1D MONDO:0010984 Autosomal recessive inheritance Uncertain Significance PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [MET], PP4 [Unmet], PP1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], BA1 [Unmet], PS1 [Unmet], PS2 [Unmet], PS4 [Unmet], PS3 [Unmet], PM5 [Unmet], PM1 [Unmet], PM3 [Unmet], PM4 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The c.9565C>T (p.Arg3189Trp) variant in CDH23 has been identified in 2 heterozygous patients with Usher syndrome without another CDH23 variant in trans (Partners LMM internal data, SCV000062996.5; PMID 22381527, 18395802). This variant was identified in 4/10120 (0.00040) Ashkenazi Jewish alleles in gnomAD. This is above the BS1 autosomal recessive threshold of 0.02% of alleles. However the filtering allele frequency of the variant is 0.00003979. Which is less than the BS1_Supporting threshold (BS1/PM2 not met). The REVEL computational prediction analysis tool produced a score of 0.8, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own. A different missense variant (p.Arg3189Gln) has been previously identified at this codon of CDH23, however this variant does not have enough evidence to support pathogenicity (PM5 not met; ClinVar Variation ID 162956). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP3. 18395802, 15660226, 22381527, 18395802, 15660226, 22381527 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA117145/MONDO:0010984/005 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 73490271 4927 A G NM_022124.5(CDH23):c.3625A>G (p.Thr1209Ala) 4927 CA137387 NM_022124.5:c.3625A>G, NC_000010.11:g.71730514A>G, CM000672.2:g.71730514A>G, NC_000010.10:g.73490271A>G, CM000672.1:g.73490271A>G, NC_000010.9:g.73160277A>G, NG_008835.1:g.338568A>G, NM_001168390.1:c.-6+7214T>C, NM_001171930.1:c.3625A>G, XM_006717940.2:c.3820A>G, XM_006717942.2:c.3754A>G, XM_011540039.1:c.3820A>G, XM_011540040.1:c.3814A>G, XM_011540041.1:c.3760A>G, XM_011540042.1:c.3820A>G, XM_011540043.1:c.3820A>G, XM_011540044.1:c.3685A>G, XM_011540045.1:c.3820A>G, XM_011540046.1:c.3280A>G, XM_011540047.1:c.2638A>G, XM_011540048.1:c.3820A>G, XM_011540049.1:c.3820A>G, XM_011540050.1:c.3820A>G, XM_011540051.1:c.3820A>G, XM_011540052.1:c.148A>G, XM_011540053.1:c.3820A>G, XR_945796.1:n.4063A>G, ENST00000224721.10:c.3640A>G, ENST00000398786.2:c.-6+7214T>C, ENST00000398792.3:n.317A>G, ENST00000398809.8:c.3622A>G, ENST00000616684.4:c.3625A>G, ENST00000622827.4:c.3625A>G, NM_022124.5(CDH23):c.3625A>G (p.Thr1209Ala) CDH23 Usher syndrome MONDO:0019501 Autosomal recessive inheritance Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BP2 [Unmet], BP3 [Unmet], BP4 [MET], BA1 [MET], BS3-Supporting [MET], PS3 [Unmet], PS4 [Unmet], PS1 [Unmet], PS2 [Unmet], PM3 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet] The filtering allele frequency (the lower threshold of the 95% CI of 3442/23972) of the c.3625A>G (p.Thr1209Ala) variant in the CDH23 gene is 13.15% for African chromosomes by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). A splicing assay did not show any impact to splicing but BS3 was not applied given no assessment of protein function (PMID:18273900). Computational prediction analysis using the metapredictor tool REVEL did not predict an impact the protein (BP4). Of note, this variant was reported in 3 patients with Usher syndrome (PMID: 15537665, 15660226, 12075507) though without any convincing evidence for pathogenicity (PM3 not met). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BS3_Supporting, BP4. 15660226, 15537665, 19683999, 12075507, 18273900, 16963483, 21569298, 21738395, 15660226, 15537665, 19683999, 12075507 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA137387/MONDO:0019501/005 0.0028 Benign Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 1 41285565 6241 G A NM_004700.3(KCNQ4):c.853G>A (p.Gly285Ser) 6241 CA340532 NM_004700.3:c.853G>A, NM_172163.2:c.853G>A, XM_011542417.1:c.853G>A, XM_011542418.1:c.853G>A, XM_011542419.1:c.853G>A, XM_011542420.1:c.853G>A, XR_946798.1:n.859G>A, XR_946799.1:n.859G>A, XR_946800.1:n.859G>A, XM_017002792.1:c.-165G>A, NM_004700.4:c.853G>A, ENST00000347132.9:c.853G>A, ENST00000443478.3:n.539G>A, ENST00000506017.1:n.172G>A, ENST00000509682.6:n.853G>A, NC_000001.11:g.40819893G>A, CM000663.2:g.40819893G>A, NC_000001.10:g.41285565G>A, CM000663.1:g.41285565G>A, NC_000001.9:g.41058152G>A, NG_008139.1:g.40882G>A, NG_008139.2:g.40882G>A, NM_004700.3(KCNQ4):c.853G>A (p.Gly285Ser) KCNQ4 nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Pathogenic PS3-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP4 [Unmet], BS2 [Unmet], PS4-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS2 [Unmet], PM5 [MET], PM1 [MET], PM4 [Unmet], PM3 [Unmet], PP1-Strong [MET], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The p.Gly285Ser variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). The p.Gly285Ser variant has been reported to segregate with hearing loss in at least 16 family members (PP1_S; PMIDs: 10025409, 25116015). The variant meets PM2 and has been observed in at least 2 affected probands (PS4_P, PMID: 10025409, Partners LMM internal data SCV000198442.4). A different pathogenic missense variant (p.Gly285Cys) has been previously identified at this codon of KCNQ4 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 6244, PMID: 10369879). Furthermore, the variant is in a location that has been defined by the ClinGen Hearing Loss Expert Panel to be a mutational hotspot or domain of KCNQ4 (PM1; PMID: 23717403; https://www.uniprot.org/uniprot/P56696). A functional study demonstrates that this variant may impact protein function (PS3_P; PMID: 10025409, 18786918). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2, PP1_S, PS4_P, PM5, PM1, PS3_P. 18786918, 10025409, 10025409, 10369879, 8035838, 10369879, 8035838, 10025409, 25116015, 10025409, 25116015 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-11 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA340532/MONDO:0019497/005 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 14 31346846 6611 C T NM_004086.2(COCH):c.151C>T (p.Pro51Ser) 6611 CA253889 NM_004086.2:c.151C>T, NC_000014.9:g.30877640C>T, CM000676.2:g.30877640C>T, NC_000014.8:g.31346846C>T, CM000676.1:g.31346846C>T, NC_000014.7:g.30416597C>T, NG_008211.2:g.8106C>T, NM_001135058.1:c.151C>T, NR_038356.1:n.1618-1088G>A, XM_011536539.1:c.151C>T, NM_001347720.1:c.346C>T, XM_017021071.1:c.346C>T, XM_024449506.1:c.151C>T, NM_004086.3:c.151C>T, ENST00000216361.8:c.151C>T, ENST00000396618.7:c.151C>T, ENST00000460581.6:c.-186C>T, ENST00000475087.5:c.151C>T, ENST00000553772.5:c.151C>T, ENST00000553833.5:n.305C>T, ENST00000555881.5:c.82+2537C>T, ENST00000556908.5:c.103C>T, ENST00000557065.1:n.67C>T, NM_004086.2(COCH):c.151C>T (p.Pro51Ser) COCH nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [MET], PP4 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS4 [MET], PS3 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], PP1-Strong [MET], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The c.151C>T (p.Pro51Ser) variant in COCH has been reported to segregate with late onset progressive hearing loss and vestibular dysfunction in > 25 family members (PP1_S; PMID: 9931344, 11332404). The variant meets PM2 and has been observed in at least 15 affected probands (PS4, PMID: 28733840, 16151338, 11332404). The allele frequency of the p.Pro51Ser variant is 0.001% (1/111716) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (PM2). Computational prediction tools and conservation analysis suggest that the p.Pro51Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_S, PS4, PM2, PP3. 11332404, 28733840, 16151338, 11332404, 25230692, 20228067, 16481359, 26256111, 12928864, 16151338, 24662630, 9931344, 16151338, 24662630, 9931344 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-19 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA253889/MONDO:0019497/005 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 1, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 14 31348132 6613 G A NM_004086.2(COCH):c.355G>A (p.Ala119Thr) 6613 CA253893 NM_004086.2:c.355G>A, NM_001135058.1:c.355G>A, NR_038356.1:n.1618-2374C>T, XM_011536539.1:c.355G>A, NM_001347720.1:c.550G>A, XM_017021071.1:c.550G>A, XM_024449506.1:c.355G>A, NM_004086.3:c.355G>A, ENST00000216361.8:c.355G>A, ENST00000396618.7:c.355G>A, ENST00000460581.6:c.19G>A, ENST00000475087.5:c.355G>A, ENST00000553772.5:c.239+1198G>A, ENST00000553833.5:n.509G>A, ENST00000555881.5:c.83-1526G>A, ENST00000556908.5:c.307G>A, ENST00000557065.1:n.156-497G>A, NC_000014.9:g.30878926G>A, CM000676.2:g.30878926G>A, NC_000014.8:g.31348132G>A, CM000676.1:g.31348132G>A, NC_000014.7:g.30417883G>A, NG_008211.2:g.9392G>A, NM_004086.2(COCH):c.355G>A (p.Ala119Thr) COCH nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BA1 [Unmet], BS3-Supporting [MET], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], PM3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The c.355G>A (p.Ala119Thr) variant in COCH has been reported in one Japanese individual with hearing loss, vestibular dysfunction, and a family history of hearing loss though no other affected family members were screened (PS4 not met; PMID: 14512963). The variant was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). A functional study demonstrates that this variant may not impact protein function (BS3_P; PMID: 25230692). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, BS3_P. 25230692, 14512963 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-17 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA253893/MONDO:0019497/005 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 1, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 89692985 7814 G T NM_000314.6(PTEN):c.469G>T (p.Glu157Ter) 7814 CA000467 NM_000314.6:c.469G>T, NC_000010.11:g.87933228G>T, CM000672.2:g.87933228G>T, NC_000010.10:g.89692985G>T, CM000672.1:g.89692985G>T, NC_000010.9:g.89682965G>T, NG_007466.2:g.74790G>T, LRG_311:g.74790G>T, NM_000314.5:c.469G>T, NM_001304717.2:c.988G>T, NM_001304718.1:c.-282G>T, XM_006717926.2:c.424G>T, XM_011539981.1:c.469G>T, XM_011539982.1:c.373G>T, XR_945789.1:n.1181G>T, XR_945790.1:n.1181G>T, XR_945791.1:n.1181G>T, NM_000314.7:c.469G>T, NM_001304717.5:c.988G>T, NM_001304718.2:c.-282G>T, ENST00000371953.7:c.469G>T, ENST00000498703.1:n.295G>T, ENST00000610634.1:c.367G>T, NM_000314.6(PTEN):c.469G>T (p.Glu157Ter) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PVS1 [MET], PM2 [MET], PS4-Supporting [MET] PTEN c.469G>T (p.E157X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 8071972) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-10-30 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000467/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89711892 7815 T A NM_000314.6(PTEN):c.510T>A (p.Ser170Arg) 7815 CA000492 NM_000314.6:c.510T>A, NC_000010.11:g.87952135T>A, CM000672.2:g.87952135T>A, NC_000010.10:g.89711892T>A, CM000672.1:g.89711892T>A, NC_000010.9:g.89701872T>A, NG_007466.2:g.93697T>A, LRG_311:g.93697T>A, NM_000314.5:c.510T>A, NM_001304717.2:c.1029T>A, NM_001304718.1:c.-82T>A, XM_006717926.2:c.465T>A, XM_011539981.1:c.510T>A, XM_011539982.1:c.414T>A, XR_945789.1:n.1381T>A, XR_945790.1:n.1498T>A, XR_945791.1:n.1205-5718T>A, NM_000314.7:c.510T>A, NM_001304717.5:c.1029T>A, NM_001304718.2:c.-82T>A, ENST00000371953.7:c.510T>A, NM_000314.6(PTEN):c.510T>A (p.Ser170Arg) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PP1 [MET], PP2 [MET], PS4-Supporting [MET], PS3 [MET], BS3 [Unmet] PTEN c.510T>A (p.S170R) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 17942903, PMID 10866302, PMID 9256433, PMID 21828076)PM2: Absent in large sequenced populations (PMID 27535533).PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 17526800, PMID 9241266)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 17526800) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000492/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692884 7816 A G NM_000314.6(PTEN):c.368A>G (p.His123Arg) 7816 CA000418 NM_000314.6:c.368A>G, NC_000010.11:g.87933127A>G, CM000672.2:g.87933127A>G, NC_000010.10:g.89692884A>G, CM000672.1:g.89692884A>G, NC_000010.9:g.89682864A>G, NG_007466.2:g.74689A>G, LRG_311:g.74689A>G, NM_000314.5:c.368A>G, NM_001304717.2:c.887A>G, NM_001304718.1:c.-383A>G, XM_006717926.2:c.323A>G, XM_011539981.1:c.368A>G, XM_011539982.1:c.272A>G, XR_945789.1:n.1080A>G, XR_945790.1:n.1080A>G, XR_945791.1:n.1080A>G, NM_000314.7:c.368A>G, NM_001304717.5:c.887A>G, NM_001304718.2:c.-383A>G, ENST00000371953.7:c.368A>G, ENST00000498703.1:n.194A>G, ENST00000610634.1:c.266A>G, NM_000314.6(PTEN):c.368A>G (p.His123Arg) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [MET], PP2 [MET], PM1 [MET] PTEN c.368A>G (p.H123R)PTEN c.368A>G (p.H123R) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations. (PMID 27535533)PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 10234502)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000418/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692886 7817 T C NM_000314.6(PTEN):c.370T>C (p.Cys124Arg) 7817 CA000422 NM_000314.6:c.370T>C, NM_000314.5:c.370T>C, NM_001304717.2:c.889T>C, NM_001304718.1:c.-381T>C, XM_006717926.2:c.325T>C, XM_011539981.1:c.370T>C, XM_011539982.1:c.274T>C, XR_945789.1:n.1082T>C, XR_945790.1:n.1082T>C, XR_945791.1:n.1082T>C, NM_000314.7:c.370T>C, NM_001304717.5:c.889T>C, NM_001304718.2:c.-381T>C, ENST00000371953.7:c.370T>C, ENST00000498703.1:n.196T>C, ENST00000610634.1:c.268T>C, NC_000010.11:g.87933129T>C, CM000672.2:g.87933129T>C, NC_000010.10:g.89692886T>C, CM000672.1:g.89692886T>C, NC_000010.9:g.89682866T>C, NG_007466.2:g.74691T>C, LRG_311:g.74691T>C, NM_000314.6(PTEN):c.370T>C (p.Cys124Arg) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PVS1 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], PS4-Supporting [MET], PM6-Strong [MET], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS2 [Unmet], PS3 [MET], PS1 [Unmet], PM1 [MET], PM5 [Unmet], PM4 [Unmet], BP7 [Unmet], BP5 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet] PTEN c.370T>C (p.Cys124Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 10866302, PMID 29706350)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor SCV000568254.4)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000568254.4) 10234502, 9467011, 9259288, 29785012, 20194734, 15987703, 29706350, 10866302 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000422/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 10 89693010 7821 T G NM_000314.6(PTEN):c.492+2T>G 7821 CA000475 NM_000314.6:c.492+2T>G, NC_000010.11:g.87933253T>G, CM000672.2:g.87933253T>G, NC_000010.10:g.89693010T>G, CM000672.1:g.89693010T>G, NC_000010.9:g.89682990T>G, NG_007466.2:g.74815T>G, LRG_311:g.74815T>G, NM_000314.5:c.492+2T>G, NM_001304717.2:c.1011+2T>G, NM_001304718.1:c.-259+2T>G, XM_006717926.2:c.447+2T>G, XM_011539981.1:c.492+2T>G, XM_011539982.1:c.396+2T>G, XR_945789.1:n.1204+2T>G, XR_945790.1:n.1204+2T>G, XR_945791.1:n.1204+2T>G, NM_000314.7:c.492+2T>G, NM_001304717.5:c.1011+2T>G, NM_001304718.2:c.-259+2T>G, ENST00000371953.7:c.492+2T>G, ENST00000498703.1:n.320T>G, ENST00000610634.1:c.390+2T>G, NM_000314.6(PTEN):c.492+2T>G PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], BS3 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.492+2T>G (IVS5+2T>G) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). 12938083, 9425889, 11875759, 9662392 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000475/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89717670 7822 CA C NM_000314.6(PTEN):c.696delA (p.Arg233Aspfs) 7822 CA000548 NM_000314.6:c.696delA, NC_000010.11:g.87957914del, CM000672.2:g.87957914del, NC_000010.10:g.89717671del, CM000672.1:g.89717671del, NC_000010.9:g.89707651del, NG_007466.2:g.99476del, LRG_311:g.99476del, NM_000314.5:c.696del, NM_000314.6:c.696del, NM_001304717.2:c.1215del, NM_001304718.1:c.105del, XM_006717926.2:c.651del, XM_011539981.1:c.696del, XM_011539982.1:c.600del, XR_945791.1:n.1266del, NM_000314.7:c.696del, NM_001304717.5:c.1215del, NM_001304718.2:c.105del, ENST00000371953.7:c.696del, ENST00000472832.2:n.123del, NM_000314.6(PTEN):c.696delA (p.Arg233Aspfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM6 [Unmet], PM2 [MET], PVS1 [MET], BS2 [Unmet], PP1 [Unmet], PP4 [Unmet], PP3 [Unmet], PP2 [Unmet], BA1 [Unmet], BP2 [Unmet], BP4 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], PS1 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS4 [Unmet], BS3 [Unmet], BS1 [Unmet], BP5 [Unmet], BP7 [Unmet] PTEN c.696delA (p.Arg233Aspfs)PTEN c.696delA (p.Arg233Aspfs) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). 9425889 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000548/MONDO:0017623/003 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89711967 7823 TC T NM_000314.6(PTEN):c.586delC (p.His196Thrfs) 7823 CA000526 NM_000314.6:c.586delC, NC_000010.11:g.87952211del, CM000672.2:g.87952211del, NC_000010.10:g.89711968del, CM000672.1:g.89711968del, NC_000010.9:g.89701948del, NG_007466.2:g.93773del, LRG_311:g.93773del, NM_000314.5:c.586del, NM_000314.6:c.586del, NM_001304717.2:c.1105del, NM_001304718.1:c.-6del, XM_006717926.2:c.541del, XM_011539981.1:c.586del, XM_011539982.1:c.490del, XR_945791.1:n.1205-5642del, NM_000314.7:c.586del, NM_001304717.5:c.1105del, NM_001304718.2:c.-6del, ENST00000371953.7:c.586del, ENST00000472832.2:n.13del, NM_000314.6(PTEN):c.586delC (p.His196Thrfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], PS4-Supporting [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.586delC (p.H196Tfs) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 9832032) 9832032 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000526/MONDO:0017623/003 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89711916 7824 TA AT NM_000314.6(PTEN):c.534_535delTAinsAT (p.Tyr178Ter) 7824 CA000509 NM_000314.6:c.534_535delTAinsAT, NC_000010.11:g.87952159_87952160delinsAT, CM000672.2:g.87952159_87952160delinsAT, NC_000010.10:g.89711916_89711917delinsAT, CM000672.1:g.89711916_89711917delinsAT, NC_000010.9:g.89701896_89701897delinsAT, NG_007466.2:g.93721_93722delinsAT, LRG_311:g.93721_93722delinsAT, NM_000314.5:c.534_535delinsAT, NM_000314.6:c.534_535delinsAT, NM_001304717.2:c.1053_1054delinsAT, NM_001304718.1:c.-58_-57delinsAT, XM_006717926.2:c.489_490delinsAT, XM_011539981.1:c.534_535delinsAT, XM_011539982.1:c.438_439delinsAT, XR_945789.1:n.1405_1406delinsAT, XR_945790.1:n.1522_1523delinsAT, XR_945791.1:n.1205-5694_1205-5693delinsAT, NM_000314.7:c.534_535delinsAT, NM_001304717.5:c.1053_1054delinsAT, NM_001304718.2:c.-58_-57delinsAT, ENST00000371953.7:c.534_535delinsAT, NM_000314.6(PTEN):c.534_535delTAinsAT (p.Tyr178Ter) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PVS1 [MET], PS4-Supporting [MET] PTEN c.534_535delTAinsAT (p.Y178X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 9832032, PMID 23335809) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000509/MONDO:0017623/003 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89653806 7825 T G NM_000314.6(PTEN):c.104T>G (p.Met35Arg) 7825 CA000268 NM_000314.6:c.104T>G, NM_000314.5:c.104T>G, NM_001304717.2:c.623T>G, NM_001304718.1:c.-602T>G, XM_006717926.2:c.104T>G, XM_011539981.1:c.104T>G, XM_011539982.1:c.68+13611T>G, XR_945789.1:n.816T>G, XR_945790.1:n.816T>G, XR_945791.1:n.816T>G, NM_000314.7:c.104T>G, NM_001304717.5:c.623T>G, NM_001304718.2:c.-602T>G, ENST00000371953.7:c.104T>G, ENST00000462694.1:n.106T>G, ENST00000610634.1:c.2T>G, NC_000010.11:g.87894049T>G, CM000672.2:g.87894049T>G, NC_000010.10:g.89653806T>G, CM000672.1:g.89653806T>G, NC_000010.9:g.89643786T>G, NG_007466.2:g.35611T>G, LRG_311:g.35611T>G, NM_000314.6(PTEN):c.104T>G (p.Met35Arg) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP2 [MET], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [MET], PS2 [MET], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet] PTEN c.104T>G (p.Met35Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (PMID 9425889)PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 9425889, 21828076, 25875300, 9425889 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000268/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89685314 7826 T C NM_000314.6(PTEN):c.209T>C (p.Leu70Pro) 7826 CA000350 NM_000314.6:c.209T>C, NM_000314.5:c.209T>C, NM_001304717.2:c.728T>C, NM_001304718.1:c.-541-5489T>C, XM_006717926.2:c.165-5489T>C, XM_011539981.1:c.209T>C, XM_011539982.1:c.113T>C, XR_945789.1:n.921T>C, XR_945790.1:n.921T>C, XR_945791.1:n.921T>C, NM_000314.7:c.209T>C, NM_001304717.5:c.728T>C, NM_001304718.2:c.-541-5489T>C, ENST00000371953.7:c.209T>C, ENST00000498703.1:n.35T>C, ENST00000610634.1:c.107T>C, NC_000010.11:g.87925557T>C, CM000672.2:g.87925557T>C, NC_000010.10:g.89685314T>C, CM000672.1:g.89685314T>C, NC_000010.9:g.89675294T>C, NG_007466.2:g.67119T>C, LRG_311:g.67119T>C, NM_000314.6(PTEN):c.209T>C (p.Leu70Pro) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP4 [Unmet], PP1 [Unmet], PS4-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [MET], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.209T>C (p.Leu70Pro) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor(s) ClinVar Organization ID: 26957) 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-11-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000350/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89717741 7828 G T NM_000314.6(PTEN):c.766G>T (p.Glu256Ter) 7828 CA000569 NM_000314.6:c.766G>T, NM_000314.5:c.766G>T, NM_001304717.2:c.1285G>T, NM_001304718.1:c.175G>T, XM_006717926.2:c.721G>T, XM_011539981.1:c.766G>T, XM_011539982.1:c.670G>T, XR_945791.1:n.1336G>T, NM_000314.7:c.766G>T, NM_001304717.5:c.1285G>T, NM_001304718.2:c.175G>T, ENST00000371953.7:c.766G>T, ENST00000472832.2:n.193G>T, NC_000010.11:g.87957984G>T, CM000672.2:g.87957984G>T, NC_000010.10:g.89717741G>T, CM000672.1:g.89717741G>T, NC_000010.9:g.89707721G>T, NG_007466.2:g.99546G>T, LRG_311:g.99546G>T, NM_000314.6(PTEN):c.766G>T (p.Glu256Ter) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PVS1 [MET], PM6 [MET], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], PS4-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.766G>T (p.E256X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 9832032)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 9832032) 9832032 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000569/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692905 7829 G A NM_000314.6(PTEN):c.389G>A (p.Arg130Gln) 7829 CA000437 NM_000314.6:c.389G>A, NC_000010.11:g.87933148G>A, CM000672.2:g.87933148G>A, NC_000010.10:g.89692905G>A, CM000672.1:g.89692905G>A, NC_000010.9:g.89682885G>A, NG_007466.2:g.74710G>A, LRG_311:g.74710G>A, NM_000314.5:c.389G>A, NM_001304717.2:c.908G>A, NM_001304718.1:c.-362G>A, XM_006717926.2:c.344G>A, XM_011539981.1:c.389G>A, XM_011539982.1:c.293G>A, XR_945789.1:n.1101G>A, XR_945790.1:n.1101G>A, XR_945791.1:n.1101G>A, NM_000314.7:c.389G>A, NM_001304717.5:c.908G>A, NM_001304718.2:c.-362G>A, ENST00000371953.7:c.389G>A, ENST00000498703.1:n.215G>A, ENST00000610634.1:c.287G>A, NM_000314.6(PTEN):c.389G>A (p.Arg130Gln) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PP2 [MET], PM6-Strong [MET], PS3 [MET], PS4 [MET], PM1 [MET] PTEN c.389G>A (p.R130Q) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6_VS: At least four assumed de novo observations in a patient with the disease and no family history. (PMID 22595938, PMID 22327138, internal laboratory contributor(s) SCV000222111.11)PS3: Phosphatase activity <50% of wild type (PMID 10866302)PS4: Probands with phenotype specificity score of 4-15.5 (PMID 26798346, PMID 17526801, PMID 23335809, PMID 22266152)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000437/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 5 Likely Pathogenic 10 89717734 7830 CAAAGT C NM_000314.6(PTEN):c.761_765delAAGTA (p.Lys254Argfs) 7830 CA000566 NM_000314.6:c.761_765delAAGTA, NM_000314.5:c.761_765del, NM_000314.6:c.761_765del, NM_001304717.2:c.1280_1284del, NM_001304718.1:c.170_174del, XM_006717926.2:c.716_720del, XM_011539981.1:c.761_765del, XM_011539982.1:c.665_669del, XR_945791.1:n.1331_1335del, NM_000314.7:c.761_765del, NM_001304717.5:c.1280_1284del, NM_001304718.2:c.170_174del, ENST00000371953.7:c.761_765del, ENST00000472832.2:n.188_192del, NC_000010.11:g.87957979_87957983del, CM000672.2:g.87957979_87957983del, NC_000010.10:g.89717736_89717740del, CM000672.1:g.89717736_89717740del, NC_000010.9:g.89707716_89707720del, NG_007466.2:g.99541_99545del, LRG_311:g.99541_99545del, NM_000314.6(PTEN):c.761_765delAAGTA (p.Lys254Argfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PVS1 [MET], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.761_765delAAGTA (p.K254Rfs) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000566/MONDO:0017623/003 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89711946 7831 T A NM_000314.6(PTEN):c.564T>A (p.Tyr188Ter) 7831 CA000521 NM_000314.6:c.564T>A, NC_000010.11:g.87952189T>A, CM000672.2:g.87952189T>A, NC_000010.10:g.89711946T>A, CM000672.1:g.89711946T>A, NC_000010.9:g.89701926T>A, NG_007466.2:g.93751T>A, LRG_311:g.93751T>A, NM_000314.5:c.564T>A, NM_001304717.2:c.1083T>A, NM_001304718.1:c.-28T>A, XM_006717926.2:c.519T>A, XM_011539981.1:c.564T>A, XM_011539982.1:c.468T>A, XR_945791.1:n.1205-5664T>A, NM_000314.7:c.564T>A, NM_001304717.5:c.1083T>A, NM_001304718.2:c.-28T>A, ENST00000371953.7:c.564T>A, NM_000314.6(PTEN):c.564T>A (p.Tyr188Ter) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet] PTEN c.564T>A (p.Y188X) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000521/MONDO:0017623/003 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89624262 7834 C CA NM_000314.6(PTEN):c.40dupA (p.Arg14Lysfs) 7834 CA254258 NM_000314.6:c.40dupA, NC_000010.11:g.87864509dup, CM000672.2:g.87864509dup, NC_000010.10:g.89624266dup, CM000672.1:g.89624266dup, NC_000010.9:g.89614246dup, NG_007466.2:g.6071dup, LRG_311:g.6071dup, NG_033079.1:g.3932dup, NM_000314.5:c.40dup, NM_000314.6:c.40dup, NM_001304717.2:c.559dup, NM_001304718.1:c.-666dup, XM_006717926.2:c.40dup, XM_011539981.1:c.40dup, XR_945789.1:n.752dup, XR_945790.1:n.752dup, XR_945791.1:n.752dup, NM_000314.7:c.40dup, NM_001304717.5:c.559dup, NM_001304718.2:c.-666dup, ENST00000371953.7:c.40dup, ENST00000462694.1:n.42dup, ENST00000487939.1:n.61dup, ENST00000610634.1:c.-63dup, ENST00000618586.1:n.9dup, NM_000314.6(PTEN):c.40dupA (p.Arg14Lysfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PM6 [MET], PVS1 [MET], PS4-Supporting [MET] PTEN c.40dupA (p.R14Kfs) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 10777358)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 10777358) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA254258/MONDO:0017623/003 0.9971 Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89720649 7839 AG A NM_000314.6(PTEN):c.802delG (p.Asp268Thrfs) 7839 CA000595 NM_000314.6:c.802delG, NM_000314.5:c.802del, NM_000314.6:c.802del, NM_001304717.2:c.1321del, NM_001304718.1:c.211del, XM_006717926.2:c.757del, XM_011539981.1:c.802del, XM_011539982.1:c.706del, XR_945791.1:n.1372del, NM_000314.7:c.802del, NM_001304717.5:c.1321del, NM_001304718.2:c.211del, ENST00000371953.7:c.802del, ENST00000472832.2:n.229del, NC_000010.11:g.87960894del, CM000672.2:g.87960894del, NC_000010.10:g.89720651del, CM000672.1:g.89720651del, NC_000010.9:g.89710631del, NG_007466.2:g.102456del, LRG_311:g.102456del, NM_000314.6(PTEN):c.802delG (p.Asp268Thrfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PVS1 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.802delG (p.Asp268Thrfs) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). 11238682, 11238682, 11238682, 11238682, 11238682, 11238682 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-07-25 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000595/MONDO:0017623/003 0.9941 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89717676 7840 G A NM_000314.6(PTEN):c.701G>A (p.Arg234Gln) 7840 CA000551 NM_000314.6:c.701G>A, NC_000010.11:g.87957919G>A, CM000672.2:g.87957919G>A, NC_000010.10:g.89717676G>A, CM000672.1:g.89717676G>A, NC_000010.9:g.89707656G>A, NG_007466.2:g.99481G>A, LRG_311:g.99481G>A, NM_000314.5:c.701G>A, NM_001304717.2:c.1220G>A, NM_001304718.1:c.110G>A, XM_006717926.2:c.656G>A, XM_011539981.1:c.701G>A, XM_011539982.1:c.605G>A, XR_945791.1:n.1271G>A, NM_000314.7:c.701G>A, NM_001304717.5:c.1220G>A, NM_001304718.2:c.110G>A, ENST00000371953.7:c.701G>A, ENST00000472832.2:n.128G>A, NM_000314.6(PTEN):c.701G>A (p.Arg234Gln) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP4 [Unmet], PP1 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] PTEN c.701G>A (p.Arg234Gln) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 12085208, 28755079, 12085208, 29785012, 29706350, 12085208, 29785012, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000551/MONDO:0017623/003 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 89685286 7841 C G NM_000314.6(PTEN):c.181C>G (p.His61Asp) 7841 CA000330 NM_000314.6:c.181C>G, NC_000010.11:g.87925529C>G, CM000672.2:g.87925529C>G, NC_000010.10:g.89685286C>G, CM000672.1:g.89685286C>G, NC_000010.9:g.89675266C>G, NG_007466.2:g.67091C>G, LRG_311:g.67091C>G, NM_000314.5:c.181C>G, NM_001304717.2:c.700C>G, NM_001304718.1:c.-541-5517C>G, XM_006717926.2:c.165-5517C>G, XM_011539981.1:c.181C>G, XM_011539982.1:c.85C>G, XR_945789.1:n.893C>G, XR_945790.1:n.893C>G, XR_945791.1:n.893C>G, NM_000314.7:c.181C>G, NM_001304717.5:c.700C>G, NM_001304718.2:c.-541-5517C>G, ENST00000371953.7:c.181C>G, ENST00000498703.1:n.7C>G, ENST00000610634.1:c.79C>G, NM_000314.6(PTEN):c.181C>G (p.His61Asp) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [MET], PVS1 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [MET], PS4 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet] PTEN c.181C>G (p.His61Asp) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 21828076, 17942903)PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 11748304)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 11748304, 11748304, 17942903, 21828076, 11748304 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-07-25 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000330/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89711886 7843 TC T NM_000314.6(PTEN):c.507delC (p.Ser170Valfs) 7843 CA000490 NM_000314.6:c.507delC, NC_000010.11:g.87952132del, CM000672.2:g.87952132del, NC_000010.10:g.89711889del, CM000672.1:g.89711889del, NC_000010.9:g.89701869del, NG_007466.2:g.93694del, LRG_311:g.93694del, NM_000314.5:c.507del, NM_000314.6:c.507del, NM_001304717.2:c.1026del, NM_001304718.1:c.-85del, XM_006717926.2:c.462del, XM_011539981.1:c.507del, XM_011539982.1:c.411del, XR_945789.1:n.1378del, XR_945790.1:n.1495del, XR_945791.1:n.1205-5721del, NM_000314.7:c.507del, NM_001304717.5:c.1026del, NM_001304718.2:c.-85del, ENST00000371953.7:c.507del, NM_000314.6(PTEN):c.507delC (p.Ser170Valfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PVS1 [MET], PM6 [MET], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [MET], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] PTEN c.507delC (p.Ser170Valfs) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 12471211)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 12471211) 12471211, 12938083, 12471211, 12471211, 12471211, 12938083 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000490/MONDO:0017623/003 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89623462 7844 G A NM_000314.6(PTEN):c.-764G>A 7844 CA000567 NM_000314.6:c.-764G>A, NC_000010.11:g.87863705G>A, CM000672.2:g.87863705G>A, NC_000010.10:g.89623462G>A, CM000672.1:g.89623462G>A, NC_000010.9:g.89613442G>A, NG_007466.2:g.5268G>A, LRG_311:g.5268G>A, NG_033079.1:g.4733C>T, NM_000314.5:c.-764G>A, NM_001304717.2:c.-245G>A, NM_001304718.1:c.-1469G>A, NM_000314.7:c.-764G>A, NM_001304717.5:c.-245G>A, NM_001304718.2:c.-1469G>A, ENST00000371953.7:c.-765G>A, ENST00000610634.1:c.-867G>A, NM_000314.6(PTEN):c.-764G>A PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET] PTEN c.-764G>A (NC_000010.10:g.89623462G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000567/MONDO:0017623/003 0.1 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89623365 7845 G T NM_000314.6(PTEN):c.-861G>T 7845 CA000612 NM_000314.6:c.-861G>T, NM_000314.5:c.-861G>T, NM_001304717.2:c.-342G>T, NM_001304718.1:c.-1566G>T, ENST00000371953.7:c.-862G>T, ENST00000610634.1:c.-964G>T, NC_000010.11:g.87863608G>T, CM000672.2:g.87863608G>T, NC_000010.10:g.89623365G>T, CM000672.1:g.89623365G>T, NC_000010.9:g.89613345G>T, NG_007466.2:g.5171G>T, LRG_311:g.5171G>T, NG_033079.1:g.4830C>A, NM_000314.6(PTEN):c.-861G>T PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], BP7 [Unmet], BP5 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.-861G>T (NC_000010.10:g.89623365G>T) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. 17847000, 17847000 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000612/MONDO:0017623/003 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692794 7848 A G NM_000314.6(PTEN):c.278A>G (p.His93Arg) 7848 CA000381 NM_000314.6:c.278A>G, NC_000010.11:g.87933037A>G, CM000672.2:g.87933037A>G, NC_000010.10:g.89692794A>G, CM000672.1:g.89692794A>G, NC_000010.9:g.89682774A>G, NG_007466.2:g.74599A>G, LRG_311:g.74599A>G, NM_000314.5:c.278A>G, NM_001304717.2:c.797A>G, NM_001304718.1:c.-473A>G, XM_006717926.2:c.233A>G, XM_011539981.1:c.278A>G, XM_011539982.1:c.182A>G, XR_945789.1:n.990A>G, XR_945790.1:n.990A>G, XR_945791.1:n.990A>G, NM_000314.7:c.278A>G, NM_001304717.5:c.797A>G, NM_001304718.2:c.-473A>G, ENST00000371953.7:c.278A>G, ENST00000498703.1:n.104A>G, ENST00000610634.1:c.176A>G, NM_000314.6(PTEN):c.278A>G (p.His93Arg) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PVS1 [Unmet], PM2 [MET], PM6 [Unmet], PP3 [Unmet], PP2 [MET], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], PS4-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS2 [MET], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [MET], PS3-Supporting [MET] PTEN c.278A>G (p.His93Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor(s) ClinVar Organization ID: 26957)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 26579216, 25647146, 20718038, 21828076, 29373119, 29785012, 29706350)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 15805158, internal laboratory contributor(s) ClinVar Organization ID: 26957) 15805158, 21194675, 24345843, 15805158, 15805158, 15805158, 25647146, 21828076, 22505997, 29785012, 20718038, 29373119, 29706350, 26579216 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-11-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000381/MONDO:0017623/003 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 5 Likely Pathogenic 10 89717730 7849 A G NM_000314.6(PTEN):c.755A>G (p.Asp252Gly) 7849 CA000564 NM_000314.6:c.755A>G, NC_000010.11:g.87957973A>G, CM000672.2:g.87957973A>G, NC_000010.10:g.89717730A>G, CM000672.1:g.89717730A>G, NC_000010.9:g.89707710A>G, NG_007466.2:g.99535A>G, LRG_311:g.99535A>G, NM_000314.5:c.755A>G, NM_001304717.2:c.1274A>G, NM_001304718.1:c.164A>G, XM_006717926.2:c.710A>G, XM_011539981.1:c.755A>G, XM_011539982.1:c.659A>G, XR_945791.1:n.1325A>G, NM_000314.7:c.755A>G, NM_001304717.5:c.1274A>G, NM_001304718.2:c.164A>G, ENST00000371953.7:c.755A>G, ENST00000472832.2:n.182A>G, NM_000314.6(PTEN):c.755A>G (p.Asp252Gly) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PVS1 [Unmet], PP4-Moderate [MET], PM2 [MET], PM6 [MET], PP3 [Unmet], PP2 [MET], PP1 [Unmet], BS2 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS2 [Unmet], PS4-Moderate [MET], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS3-Supporting [MET] PTEN c.755A>G (p.D252G) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 23335809, personal communication with corresponding author)PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 23335809, 15805158)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 21828076, 29706633, 25527629, 29706350) 21659347, 17286265, 21194675, 23335809, 15805158, 21828076, 29706633, 29373119, 25527629, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-07-25 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000564/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 10 89717697 7850 T C NM_000314.6(PTEN):c.722T>C (p.Phe241Ser) 7850 CA000555 NM_000314.6:c.722T>C, NC_000010.11:g.87957940T>C, CM000672.2:g.87957940T>C, NC_000010.10:g.89717697T>C, CM000672.1:g.89717697T>C, NC_000010.9:g.89707677T>C, NG_007466.2:g.99502T>C, LRG_311:g.99502T>C, NM_000314.5:c.722T>C, NM_001304717.2:c.1241T>C, NM_001304718.1:c.131T>C, XM_006717926.2:c.677T>C, XM_011539981.1:c.722T>C, XM_011539982.1:c.626T>C, XR_945791.1:n.1292T>C, NM_000314.7:c.722T>C, NM_001304717.5:c.1241T>C, NM_001304718.2:c.131T>C, ENST00000371953.7:c.722T>C, ENST00000472832.2:n.149T>C, NM_000314.6(PTEN):c.722T>C (p.Phe241Ser) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM6 [Unmet], PM2 [MET], PVS1 [Unmet], BS2 [Unmet], PP1 [Unmet], PP3 [Unmet], PP2 [MET], PP4 [Unmet], PS4-Supporting [MET], BP2 [Unmet], BP4 [Unmet], BA1 [Unmet], PS2 [Unmet], PS3 [MET], PS1 [Unmet], BS4 [Unmet], BS3 [Unmet], BS1 [Unmet], BP5 [Unmet], BP7 [Unmet], PM1 [Unmet], PM4 [Unmet], PM5 [Unmet] PTEN c.722T>C (p.Phe241Ser) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350, 29785012, 26579216, 25527629, 21828076)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 15805158) 15805158, 21194675, 15805158, 29785012, 26579216, 25527629, 29373119, 29706350, 25937288, 21828076 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-11-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000555/MONDO:0017623/003 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 19 4117550 8272 A C NM_030662.3(MAP2K2):c.170T>G (p.Phe57Cys) 8272 CA279958 NM_030662.3:c.170T>G, LRG_750t1:c.170T>G, XM_006722799.2:c.170T>G, XM_017026989.1:c.170T>G, XM_017026990.1:c.170T>G, XM_017026991.1:c.170T>G, ENST00000262948.9:c.170T>G, ENST00000394867.8:c.-122T>G, ENST00000599345.1:n.367T>G, NC_000019.10:g.4117552A>C, CM000681.2:g.4117552A>C, NC_000019.9:g.4117550A>C, CM000681.1:g.4117550A>C, NC_000019.8:g.4068550A>C, NG_007996.1:g.11577T>G, LRG_750:g.11577T>G, NM_030662.3(MAP2K2):c.170T>G (p.Phe57Cys) MAP2K2 cardiofaciocutaneous syndrome MONDO:0015280 Autosomal dominant inheritance Pathogenic PP3 [MET], PP2 [MET], PM5 [MET], PM1 [MET], PS3 [MET], PM6 [MET], PM2 [MET] The c.170T>G (p.Phe57Cys) variant in MAP2K2 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 16439621). In vitro functional studies provide some evidence that the p.Phe57Cys variant may impact protein function (PS3; PMID 16439621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). A different pathogenic missense variant has been previously identified at this codon of MAP2K2 (p.Phe57Val for malignant melanoma) which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 8273). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe57Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS3, PM2, PM5, PP2, PM1, PP3. 16439621 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA279958/MONDO:0015280/004 0.9749 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 19 4117551 8273 A C NM_030662.3(MAP2K2):c.169T>G (p.Phe57Val) 8273 CA279960 NM_030662.3:c.169T>G, NC_000019.10:g.4117553A>C, CM000681.2:g.4117553A>C, NC_000019.9:g.4117551A>C, CM000681.1:g.4117551A>C, NC_000019.8:g.4068551A>C, NG_007996.1:g.11576T>G, LRG_750:g.11576T>G, LRG_750t1:c.169T>G, XM_006722799.2:c.169T>G, XM_017026989.1:c.169T>G, XM_017026990.1:c.169T>G, XM_017026991.1:c.169T>G, ENST00000262948.9:c.169T>G, ENST00000394867.8:c.-123T>G, ENST00000599345.1:n.366T>G, NM_030662.3(MAP2K2):c.169T>G (p.Phe57Val) MAP2K2 cardiofaciocutaneous syndrome MONDO:0015280 Autosomal dominant inheritance Pathogenic PP2 [MET], PP3 [MET], PM1 [MET], PS2-Very Strong [MET], PM2 [MET] The c.169T>G (p.Phe57Val) variant in MAP2K2 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 18042262). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe57Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PM1, PM2, PP2, PP3. 18042262 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA279960/MONDO:0015280/004 0.9749 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 19 4110574 8275 G T NM_030662.3(MAP2K2):c.383C>A (p.Pro128Gln) 8275 CA279962 NM_030662.3:c.383C>A, LRG_750t1:c.383C>A, XM_006722799.2:c.383C>A, XM_017026989.1:c.383C>A, XM_017026990.1:c.383C>A, XM_017026991.1:c.383C>A, ENST00000262948.9:c.383C>A, ENST00000394867.8:c.92C>A, ENST00000599345.1:n.580C>A, NC_000019.10:g.4110576G>T, CM000681.2:g.4110576G>T, NC_000019.9:g.4110574G>T, CM000681.1:g.4110574G>T, NC_000019.8:g.4061574G>T, NG_007996.1:g.18553C>A, LRG_750:g.18553C>A, NM_030662.3(MAP2K2):c.383C>A (p.Pro128Gln) MAP2K2 cardiofaciocutaneous syndrome MONDO:0015280 Autosomal dominant inheritance Pathogenic PP1 [MET], PP3 [MET], PP2 [MET], PM1 [MET], PS3 [MET], PM2 [MET] The c.383C>A (p.Pro128Gln) variant in MAP2K2 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 20358587). In vitro functional studies provide some evidence that the p.Pro128Gln variant may impact protein function (PS3; PMID 20358587). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Pro128Gln variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP1_Strong, PS3, PM1, PM2, PP2, PP3. 20358587 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA279962/MONDO:0015280/004 0.9941 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 11 76869378 11852 G A NM_000260.3(MYO7A):c.905G>A (p.Arg302His) 11852 CA132454 NM_000260.3:c.905G>A, NM_001127179.2:c.905G>A, NM_001127180.1:c.905G>A, XM_005274012.2:c.905G>A, XM_006718558.2:c.905G>A, XM_006718559.2:c.905G>A, XM_006718560.2:c.905G>A, XM_006718561.2:c.905G>A, XM_011545044.1:c.905G>A, XM_011545045.1:c.905G>A, XM_011545046.1:c.872G>A, XM_011545047.1:c.905G>A, XM_011545048.1:c.905G>A, XM_011545049.1:c.849+940G>A, XM_011545050.1:c.647G>A, XM_011545051.1:c.905G>A, XM_011545052.1:c.905G>A, XR_949938.1:n.1225G>A, XR_949941.1:n.1225G>A, XR_949942.1:n.1227G>A, XR_949943.1:n.1227G>A, XM_011545044.2:c.905G>A, XM_011545046.2:c.995G>A, XM_011545050.2:c.647G>A, XM_017017778.1:c.995G>A, XM_017017779.1:c.995G>A, XM_017017780.1:c.995G>A, XM_017017781.1:c.995G>A, XM_017017782.1:c.995G>A, XM_017017783.1:c.995G>A, XM_017017784.1:c.995G>A, XM_017017785.1:c.939+940G>A, XM_017017786.1:c.995G>A, XM_017017787.1:c.995G>A, XM_017017788.1:c.995G>A, XR_001747885.1:n.1010G>A, XR_001747886.1:n.1010G>A, XR_001747887.1:n.1010G>A, XR_001747888.1:n.1010G>A, XR_001747889.1:n.1010G>A, NM_000260.4:c.905G>A, ENST00000409619.6:c.872G>A, ENST00000409709.7:c.905G>A, ENST00000409893.5:c.905G>A, ENST00000458637.6:c.905G>A, ENST00000620575.4:c.905G>A, NC_000011.10:g.77158332G>A, CM000673.2:g.77158332G>A, NC_000011.9:g.76869378G>A, CM000673.1:g.76869378G>A, NC_000011.8:g.76547026G>A, NG_009086.1:g.35069G>A, NM_000260.3(MYO7A):c.905G>A (p.Arg302His) MYO7A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Likely Benign BS3-Supporting [MET], BP2 [MET], BP5 [Unmet], BS1 [MET] The filtering allele frequency of the c.905G>A (p.Arg302His) variant in the MYO7A gene is 0.4% for European chromosomes by gnomAD (587/126276 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). While this variant has been reported in several individuals with Usher syndrome, in 2 individuals it was identified in cis with another pathogenic MYO7A variant (BP2; PMID 8900236). This variant has also been reported in at least 2 additional individuals with Usher syndrome who had alternate genetic etiologies identified (PMID: 25468891). In addition, in vitro functional evidence from one study suggests that the Arg302His variant had little effect on motor activity of MYO7A (BS3_Supporting PMID: 18700726). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1, BP2, BS3_Supporting. 18700726, 8900236, 25468891 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-10-22 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA132454/MONDO:0019501/005 0.3246 Likely Pathogenic Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 3 Uncertain Significance 16 68856041 12232 G A NM_004360.4(CDH1):c.1849G>A (p.Ala617Thr) 12232 CA121991 NM_004360.4:c.1849G>A, NM_004360.3:c.1849G>A, LRG_301t1:c.1849G>A, XM_011523488.1:c.1114G>A, XM_011523489.1:c.1114G>A, NM_001317184.1:c.1666G>A, NM_001317185.1:c.301G>A, NM_001317186.1:c.-117G>A, ENST00000261769.9:c.1849G>A, ENST00000422392.6:c.1666G>A, ENST00000562836.5:n.1920G>A, ENST00000566510.5:c.*515G>A, ENST00000566612.5:c.*89G>A, ENST00000611625.4:c.1912G>A, ENST00000612417.4:c.1830+19G>A, ENST00000621016.4:c.1849G>A, NC_000016.10:g.68822138G>A, CM000678.2:g.68822138G>A, NC_000016.9:g.68856041G>A, CM000678.1:g.68856041G>A, NC_000016.8:g.67413542G>A, NG_008021.1:g.89847G>A, LRG_301:g.89847G>A, NM_004360.4(CDH1):c.1849G>A (p.Ala617Thr) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BA1 [MET], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.1849G>A (p.Ala617Thr) variant has an allele frequency of 0.04479 (4.5%, 1076/24,022 alleles) in the African subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA121991/MONDO:0007648/007 0.0014 Benign Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 16 68867265 12233 A G NM_004360.4(CDH1):c.2512A>G (p.Ser838Gly) 12233 CA121994 NM_004360.4:c.2512A>G, NM_004360.3:c.2512A>G, LRG_301t1:c.2512A>G, XM_011523488.1:c.1777A>G, XM_011523489.1:c.1777A>G, NM_001317184.1:c.2329A>G, NM_001317185.1:c.964A>G, NM_001317186.1:c.547A>G, ENST00000261769.9:c.2512A>G, ENST00000422392.6:c.2329A>G, ENST00000562118.1:n.730A>G, ENST00000562836.5:n.2583A>G, ENST00000566510.5:c.*1178A>G, ENST00000566612.5:c.*752A>G, ENST00000611625.4:c.2575A>G, ENST00000612417.4:c.1854-829A>G, ENST00000621016.4:c.1866-841A>G, NC_000016.10:g.68833362A>G, CM000678.2:g.68833362A>G, NC_000016.9:g.68867265A>G, CM000678.1:g.68867265A>G, NC_000016.8:g.67424766A>G, NG_008021.1:g.101071A>G, LRG_301:g.101071A>G, NM_004360.4(CDH1):c.2512A>G (p.Ser838Gly) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Uncertain Significance BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [MET], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.2512A>G (p.Ser838Gly) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). There is no other supporting data that meet criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA121994/MONDO:0007648/007 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 16 68855984 12241 C T NM_004360.4(CDH1):c.1792C>T (p.Arg598Ter) 12241 CA281000 NM_004360.4:c.1792C>T, NM_004360.3:c.1792C>T, LRG_301t1:c.1792C>T, XM_011523488.1:c.1057C>T, XM_011523489.1:c.1057C>T, NM_001317184.1:c.1609C>T, NM_001317185.1:c.244C>T, NM_001317186.1:c.-174C>T, ENST00000261769.9:c.1792C>T, ENST00000422392.6:c.1609C>T, ENST00000562836.5:n.1863C>T, ENST00000566510.5:c.*458C>T, ENST00000566612.5:c.*32C>T, ENST00000611625.4:c.1855C>T, ENST00000612417.4:c.1792C>T, ENST00000621016.4:c.1792C>T, NC_000016.10:g.68822081C>T, CM000678.2:g.68822081C>T, NC_000016.9:g.68855984C>T, CM000678.1:g.68855984C>T, NC_000016.8:g.67413485C>T, NG_008021.1:g.89790C>T, LRG_301:g.89790C>T, NM_004360.4(CDH1):c.1792C>T (p.Arg598Ter) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [MET], PM2 [MET], PM6 [Unmet], PP3 [Unmet], BS2 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS2 [MET], PS3 [Unmet], PS4 [MET], PS1 [Unmet], PP1-Strong [MET] The c.1792C>T (p.Arg598*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 21696387, 16061854, 11419427 and SCV000275702.5). This variant has also been reported in at least four families meeting HDGC clinical criteria (PS4_Strong; PMID: 9751616, 21696387, 16061854, 11419427). There is one known de novo observation of this variant with parental confirmation in a patient with diffuse gastric cancer and/or lobular breast cancer (PS2; PMID: 21696387). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1, PM2, PP1_Strong, PS4, PS2. 21696387, 16061854, 21696387, 9751616, 16061854, 11419427, 21696387, 16061854 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA281000/MONDO:0007648/007 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68846047 12245 A G NM_004360.4(CDH1):c.1018A>G (p.Thr340Ala) 12245 CA288016 NM_004360.4:c.1018A>G, NM_004360.3:c.1018A>G, LRG_301t1:c.1018A>G, XM_011523488.1:c.283A>G, XM_011523489.1:c.283A>G, NM_001317184.1:c.1018A>G, NM_001317185.1:c.-598A>G, NM_001317186.1:c.-802A>G, ENST00000261769.9:c.1018A>G, ENST00000422392.6:c.1018A>G, ENST00000561751.1:n.640A>G, ENST00000562836.5:n.1089A>G, ENST00000565810.1:n.62A>G, ENST00000566510.5:c.862A>G, ENST00000566612.5:c.1018A>G, ENST00000611625.4:c.1018A>G, ENST00000612417.4:c.1018A>G, ENST00000621016.4:c.1018A>G, NC_000016.10:g.68812144A>G, CM000678.2:g.68812144A>G, NC_000016.9:g.68846047A>G, CM000678.1:g.68846047A>G, NC_000016.8:g.67403548A>G, NG_008021.1:g.79853A>G, LRG_301:g.79853A>G, NM_004360.4(CDH1):c.1018A>G (p.Thr340Ala) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BA1 [MET], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.1018A>G (p.Thr340Ala) variant has an allele frequency of 0.00360 (0.36%, 68/18,866 alleles) in the East Asian subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA288016/MONDO:0007648/007 0.6752 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 0, 0] 1 Uncertain Significance 12 25398304 12594 T A NM_004985.4(KRAS):c.15A>T (p.Lys5Asn) 12594 CA234191 NM_004985.4:c.15A>T, NM_033360.3:c.15A>T, XM_006719069.2:c.15A>T, XM_011520653.1:c.15A>T, XM_006719069.4:c.15A>T, XM_011520653.3:c.15A>T, ENST00000256078.8:c.15A>T, ENST00000311936.7:c.15A>T, ENST00000556131.1:c.15A>T, ENST00000557334.5:c.15A>T, NC_000012.12:g.25245370T>A, CM000674.2:g.25245370T>A, NC_000012.11:g.25398304T>A, CM000674.1:g.25398304T>A, NC_000012.10:g.25289571T>A, NG_007524.1:g.10551A>T, NM_004985.4(KRAS):c.15A>T (p.Lys5Asn) KRAS Noonan syndrome MONDO:0018997 Autosomal dominant inheritance Pathogenic PP3 [MET], PP2 [MET], PM6-Strong [MET], PS4-Moderate [MET], PM2 [MET] The c.15A>T (p.Lys5Asn) variant in KRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data GTR ID: 26957, 506381 PMID 17056636). The variant has been detected in This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The p.Lys5Asn variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; EGL genetics internal data GTR ID: 500060; PMID: 17056636; ClinVar SCV000202928.6). Computational prediction tools and conservation analysis suggest that the p.Lys5Asn variant may impact the protein (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PM2, PS4_Moderate, PP3, PP2) 17056636, 17056636 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA234191/MONDO:0018997/004 0.9941 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 11 534289 12602 C T NM_005343.3(HRAS):c.34G>A (p.Gly12Ser) 12602 CA122549 NM_005343.3:c.34G>A, NC_000011.10:g.534289C>T, CM000673.2:g.534289C>T, NC_000011.9:g.534289C>T, CM000673.1:g.534289C>T, NC_000011.8:g.524289C>T, NG_007666.1:g.6262G>A, NM_001130442.1:c.34G>A, NM_005343.2:c.34G>A, NM_176795.3:c.34G>A, XM_011519875.1:c.-424-4309C>T, XM_011519877.1:c.-161-5291C>T, XR_242795.1:n.233G>A, NM_001130442.2:c.34G>A, NM_001318054.1:c.-286G>A, NM_176795.4:c.34G>A, XM_011519875.2:c.-424-4309C>T, XM_011519877.2:c.-161-5291C>T, XM_017017167.1:c.-499-4234C>T, XM_017017168.1:c.-499-4234C>T, NM_005343.4:c.34G>A, ENST00000311189.7:c.34G>A, ENST00000397594.5:c.34G>A, ENST00000397596.6:c.34G>A, ENST00000417302.5:c.34G>A, ENST00000451590.5:c.34G>A, ENST00000468682.2:n.522G>A, ENST00000482021.1:n.157G>A, ENST00000493230.5:c.34G>A, NM_005343.3(HRAS):c.34G>A (p.Gly12Ser) LRRC56 Costello syndrome MONDO:0009026 Autosomal dominant inheritance Pathogenic PP3 [MET], PP2 [MET], PM1 [MET], PS4 [MET], PS3 [MET], PS2-Very Strong [MET], PM2 [MET] The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16170316, 16835863, 16443854, 16835863, 16881968, 17054105, 19669404). The p.Gly12Ser variant has been identified in >5 independent occurrences in patients with clinical features of a RASopathy (PS4; PMID: 20660566, 16372351, 16329078, 16969868, 18039947, 19371735, 19206176, 16835863). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). Computational prediction tools and conservation analysis suggest that the p.Gly12Ser variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1, PM2, PP2, PP3. 29493581, 19206176, 19371735, 16329078, 16372351, 16969868, 16835863, 20660566, 18039947, 17412879, 17054105, 16443854, 19669404, 16170316, 16881968, 16835863 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA122549/MONDO:0009026/004 0.9941 Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 11 533553 12605 T C NM_005343.3(HRAS):c.350A>G (p.Lys117Arg) 12605 CA256490 NM_005343.3:c.350A>G, NM_001130442.1:c.350A>G, NM_005343.2:c.350A>G, NM_176795.3:c.350A>G, XM_011519875.1:c.-424-5045T>C, XM_011519877.1:c.-162+5216T>C, XR_242795.1:n.549A>G, NM_001130442.2:c.350A>G, NM_001318054.1:c.31A>G, NM_176795.4:c.350A>G, XM_011519875.2:c.-424-5045T>C, XM_011519877.2:c.-162+5216T>C, XM_017017167.1:c.-499-4970T>C, XM_017017168.1:c.-499-4970T>C, NM_005343.4:c.350A>G, ENST00000311189.7:c.350A>G, ENST00000397594.5:c.350A>G, ENST00000397596.6:c.350A>G, ENST00000417302.5:c.350A>G, ENST00000451590.5:c.350A>G, ENST00000462734.1:n.43A>G, ENST00000478324.5:n.60A>G, ENST00000479482.1:n.271A>G, ENST00000493230.5:c.350A>G, NC_000011.10:g.533553T>C, CM000673.2:g.533553T>C, NC_000011.9:g.533553T>C, CM000673.1:g.533553T>C, NC_000011.8:g.523553T>C, NG_007666.1:g.6998A>G, NM_005343.3(HRAS):c.350A>G (p.Lys117Arg) LRRC56 Costello syndrome MONDO:0009026 Autosomal dominant inheritance Pathogenic PP3 [MET], PM6-Strong [MET], PM1 [MET], PS3 [MET], PM2 [MET] The c.350A>G (p.Lys117Arg) variant in HRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16443854, 16155195). In vitro functional studies provide some evidence that the p.Lys117Arg variant may impact protein function (PS3; PMID 17979197, 21850009). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Lys117Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM1, PM2, PP3. 16443854, 29493581, 21850009 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA256490/MONDO:0009026/004 0.9941 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 11 534286 12606 C A NM_005343.3(HRAS):c.37G>T (p.Gly13Cys) 12606 CA295247 NM_005343.3:c.37G>T, NM_001130442.1:c.37G>T, NM_005343.2:c.37G>T, NM_176795.3:c.37G>T, XM_011519875.1:c.-424-4312C>A, XM_011519877.1:c.-161-5294C>A, XR_242795.1:n.236G>T, NM_001130442.2:c.37G>T, NM_001318054.1:c.-283G>T, NM_176795.4:c.37G>T, XM_011519875.2:c.-424-4312C>A, XM_011519877.2:c.-161-5294C>A, XM_017017167.1:c.-499-4237C>A, XM_017017168.1:c.-499-4237C>A, NM_005343.4:c.37G>T, ENST00000311189.7:c.37G>T, ENST00000397594.5:c.37G>T, ENST00000397596.6:c.37G>T, ENST00000417302.5:c.37G>T, ENST00000451590.5:c.37G>T, ENST00000468682.2:n.525G>T, ENST00000482021.1:n.160G>T, ENST00000493230.5:c.37G>T, NC_000011.10:g.534286C>A, CM000673.2:g.534286C>A, NC_000011.9:g.534286C>A, CM000673.1:g.534286C>A, NC_000011.8:g.524286C>A, NG_007666.1:g.6265G>T, NM_005343.3(HRAS):c.37G>T (p.Gly13Cys) LRRC56 Noonan syndrome MONDO:0018997 Autosomal dominant inheritance Pathogenic PP3 [MET], PP2 [MET], PM1 [MET], PS4-Moderate [MET], PS2-Very Strong [MET], PM2 [MET] The c.37G>T (p.Gly13Cys) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 21438134, 16329078). The p.Gly13Cys variant has been identified in at least 3 other independent occurrence in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 16372351). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly13Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3, PM1, PM2, PS4_Moderate, PS2_VeryStrong. 29493581, 16329078, 21438134 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA295247/MONDO:0018997/004 0.9941 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 11 533883 12610 G A NM_176795.4(HRAS):c.173C>T (p.Thr58Ile) 12610 CA341206 NM_176795.4:c.173C>T, NM_001130442.1:c.173C>T, NM_005343.2:c.173C>T, NM_176795.3:c.173C>T, XM_011519875.1:c.-424-4715G>A, XM_011519877.1:c.-162+5546G>A, XR_242795.1:n.372C>T, NM_001130442.2:c.173C>T, NM_001318054.1:c.-147C>T, NM_005343.3:c.173C>T, XM_011519875.2:c.-424-4715G>A, XM_011519877.2:c.-162+5546G>A, XM_017017167.1:c.-499-4640G>A, XM_017017168.1:c.-499-4640G>A, NM_005343.4:c.173C>T, ENST00000311189.7:c.173C>T, ENST00000397594.5:c.173C>T, ENST00000397596.6:c.173C>T, ENST00000417302.5:c.173C>T, ENST00000451590.5:c.173C>T, ENST00000468682.2:n.661C>T, ENST00000479482.1:n.94C>T, ENST00000493230.5:c.173C>T, NC_000011.10:g.533883G>A, CM000673.2:g.533883G>A, NC_000011.9:g.533883G>A, CM000673.1:g.533883G>A, NC_000011.8:g.523883G>A, NG_007666.1:g.6668C>T, NM_176795.4(HRAS):c.173C>T (p.Thr58Ile) LRRC56 Costello syndrome MONDO:0009026 Autosomal dominant inheritance Pathogenic PP3 [MET], PP2 [MET], PS4-Supporting [MET], PM1 [MET], PS1 [MET], PM6 [MET], PM2 [MET] The c.173C>T (p.Thr58Ile) variant in HRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 20112233, 16474405). Also, at least 2 independent occurrences of this variant have been detected in patients with a RASopathy (PS4_Supporting; PMID: 22488832, 18247425, 23321623, 20949621, 16921267). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicities of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup (PS1; 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). The variant is in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS4_Supporting, PM2, PS1, PM1, PP2, PP3. 18247425, 16921267, 23321623, 22488832, 20949621, 20112233, 16474405 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA341206/MONDO:0009026/004 0.9941 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 15 66727442 13350 T C NM_002755.3(MAP2K1):c.158T>C (p.Phe53Ser) 13350 CA279966 NM_002755.3:c.158T>C, LRG_725t1:c.158T>C, XM_011521783.1:c.92T>C, XM_011521783.3:c.92T>C, XM_017022411.2:c.158T>C, XM_017022412.1:c.92T>C, ENST00000307102.9:c.158T>C, ENST00000425818.2:n.669T>C, NC_000015.10:g.66435104T>C, CM000677.2:g.66435104T>C, NC_000015.9:g.66727442T>C, CM000677.1:g.66727442T>C, NC_000015.8:g.64514496T>C, NG_008305.1:g.53232T>C, LRG_725:g.53232T>C, NM_002755.3(MAP2K1):c.158T>C (p.Phe53Ser) MAP2K1 cardiofaciocutaneous syndrome MONDO:0015280 Autosomal dominant inheritance Pathogenic PP3 [MET], PP2 [MET], PM1 [MET], PS3 [MET], PM6 [MET], PM2 [MET] The c.158T>C (p.Phe53Ser) variant in MAP2K1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 16439621). In vitro functional studies provide some evidence that the p.Phe53Ser variant may impact protein function (PS3; PMID 16439621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe53Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM6, PS3, PM2, PP2, PM1, PP3. 16439621, 16439621 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA279966/MONDO:0015280/004 0.9749 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 1, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36253011 14463 C A NM_001754.4(RUNX1):c.352-1G>T 14463 CA248609 NM_001754.4:c.352-1G>T, NM_001001890.2:c.271-1G>T, NM_001122607.1:c.271-1G>T, LRG_482t1:c.352-1G>T, XM_005261068.3:c.316-1G>T, XM_005261069.3:c.352-1G>T, XM_011529766.1:c.352-1G>T, XM_011529767.1:c.313-1G>T, XM_011529768.1:c.313-1G>T, XM_011529770.1:c.352-1G>T, XR_937576.1:n.531-1G>T, XM_005261069.4:c.352-1G>T, XM_011529766.2:c.352-1G>T, XM_011529767.2:c.313-1G>T, XM_011529768.2:c.313-1G>T, XM_011529770.2:c.352-1G>T, XM_017028487.1:c.199-1G>T, XR_937576.2:n.578-1G>T, ENST00000300305.7:c.352-1G>T, ENST00000344691.8:c.271-1G>T, ENST00000358356.9:c.271-1G>T, ENST00000399237.6:c.316-1G>T, ENST00000399240.5:c.271-1G>T, ENST00000437180.5:c.352-1G>T, ENST00000455571.5:c.313-1G>T, ENST00000482318.5:c.59-1G>T, NC_000021.9:g.34880714C>A, CM000683.2:g.34880714C>A, NC_000021.8:g.36253011C>A, CM000683.1:g.36253011C>A, NC_000021.7:g.35174881C>A, NG_011402.2:g.1108998G>T, LRG_482:g.1108998G>T, NM_001754.4(RUNX1):c.352-1G>T RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP1-Strong [MET], PP3 [Unmet], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [MET] The NM_001754.4:c.352-1G>T variant is a canonical splice site variant that is predicted to introduce a frameshift and a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1; PMID: 10508512). This variant was found to co-segregate with disease in multiple affected family members, with more than seven meioses (at least 25 affected individuals) observed in one family/across X families (PP1_Strong; 10508512). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PP1_Strong, PM2, PS4_Supporting. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA248609/MONDO:0011071/008 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36231782 14464 C T NM_001754.4(RUNX1):c.602G>A (p.Arg201Gln) 14464 CA248610 NM_001754.4:c.602G>A, NM_001001890.2:c.521G>A, NM_001122607.1:c.521G>A, LRG_482t1:c.602G>A, XM_005261068.3:c.566G>A, XM_005261069.3:c.602G>A, XM_011529766.1:c.602G>A, XM_011529767.1:c.563G>A, XM_011529768.1:c.563G>A, XM_011529770.1:c.602G>A, XR_937576.1:n.781G>A, XM_005261069.4:c.602G>A, XM_011529766.2:c.602G>A, XM_011529767.2:c.563G>A, XM_011529768.2:c.563G>A, XM_011529770.2:c.602G>A, XM_017028487.1:c.449G>A, XR_937576.2:n.828G>A, ENST00000300305.7:c.602G>A, ENST00000344691.8:c.521G>A, ENST00000358356.9:c.521G>A, ENST00000399237.6:c.566G>A, ENST00000399240.5:c.521G>A, ENST00000437180.5:c.602G>A, ENST00000467577.1:n.94G>A, ENST00000482318.5:c.*192G>A, NC_000021.9:g.34859485C>T, CM000683.2:g.34859485C>T, NC_000021.8:g.36231782C>T, CM000683.1:g.36231782C>T, NC_000021.7:g.35153652C>T, NG_011402.2:g.1130227G>A, LRG_482:g.1130227G>A, NM_001754.4(RUNX1):c.602G>A (p.Arg201Gln) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [MET], PS1 [Unmet], PS4 [MET], PM4 [Unmet], PM1 [MET], PM5 [Unmet], BP7 [Unmet], BS3 [Unmet], BS4 [Unmet], BS1 [Unmet], PP3 [MET], PP1 [MET], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.602G>A (p.Arg201Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 17290219, 11830488, 23817177, 22318203, 25840971, 23848403). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMID: 27112265, 28748566, 10508512). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). The variant has a REVEL score >0.75 (0.94) (PP3). It was found to co-segregate with disease in multiple affected family members, with four meioses observed in across 3 families (PP1; PMID: 27112265, 28748566, 10508512). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PS4, PM1, PM2, PP1, PP3. 23817177, 22318203, 11830488, 23848403, 17290219, 25840971, 27112265, 10508512, 28748566, 27112265, 10508512, 28748566, 27112265, 10508512, 28748566 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA248610/MONDO:0011071/008 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 21 36259163 14465 T C NM_001754.4(RUNX1):c.328A>G (p.Lys110Glu) 14465 CA248613 NM_001754.4:c.328A>G, NC_000021.9:g.34886866T>C, CM000683.2:g.34886866T>C, NC_000021.8:g.36259163T>C, CM000683.1:g.36259163T>C, NC_000021.7:g.35181033T>C, NG_011402.2:g.1102846A>G, LRG_482:g.1102846A>G, NM_001001890.2:c.247A>G, NM_001122607.1:c.247A>G, LRG_482t1:c.328A>G, XM_005261068.3:c.292A>G, XM_005261069.3:c.328A>G, XM_011529766.1:c.328A>G, XM_011529767.1:c.289A>G, XM_011529768.1:c.289A>G, XM_011529770.1:c.328A>G, XR_937576.1:n.507A>G, XM_005261069.4:c.328A>G, XM_011529766.2:c.328A>G, XM_011529767.2:c.289A>G, XM_011529768.2:c.289A>G, XM_011529770.2:c.328A>G, XM_017028487.1:c.175A>G, XR_937576.2:n.554A>G, ENST00000300305.7:c.328A>G, ENST00000344691.8:c.247A>G, ENST00000358356.9:c.247A>G, ENST00000399237.6:c.292A>G, ENST00000399240.5:c.247A>G, ENST00000437180.5:c.328A>G, ENST00000455571.5:c.289A>G, ENST00000482318.5:c.59-6153A>G, NM_001754.4(RUNX1):c.328A>G (p.Lys110Glu) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [MET], PM5 [Unmet], PM4 [Unmet], PM1 [MET], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], PP1-Strong [MET], PP3 [MET], PS4-Supporting [MET], PVS1 [Unmet], PM2 [MET], PM6 [Unmet] Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.328A>G (p.Lys110Glu) variant and data from secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 23848403; 17290219; 11830488). This variant was found to co-segregate with disease in multiple affected family members, with 7 meioses observed in one pedigree (PP1_Strong; PMID: 11830488). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score >0.75 (0.953) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PP1_Strong, PM1, PM2, PP3, PS4_Supporting. 11830488, 23848403, 17290219, 11830488, 11830488, 11830488 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA248613/MONDO:0011071/008 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36252850 14466 GT G NM_001754.4(RUNX1):c.508+3delA 14466 CA248618 NM_001754.4:c.508+3delA, NM_001001890.2:c.427+3del, NM_001122607.1:c.427+3del, NM_001754.4:c.508+3del, LRG_482t1:c.508+3del, XM_005261068.3:c.472+3del, XM_005261069.3:c.508+3del, XM_011529766.1:c.508+3del, XM_011529767.1:c.469+3del, XM_011529768.1:c.469+3del, XM_011529770.1:c.508+3del, XR_937576.1:n.687+3del, XM_005261069.4:c.508+3del, XM_011529766.2:c.508+3del, XM_011529767.2:c.469+3del, XM_011529768.2:c.469+3del, XM_011529770.2:c.508+3del, XM_017028487.1:c.355+3del, XR_937576.2:n.734+3del, ENST00000300305.7:c.508+3del, ENST00000344691.8:c.427+3del, ENST00000358356.9:c.427+3del, ENST00000399237.6:c.472+3del, ENST00000399240.5:c.427+3del, ENST00000437180.5:c.508+3del, ENST00000482318.5:c.*98+3del, NC_000021.9:g.34880554del, CM000683.2:g.34880554del, NC_000021.8:g.36252851del, CM000683.1:g.36252851del, NC_000021.7:g.35174721del, NG_011402.2:g.1109158del, LRG_482:g.1109158del, NM_001754.4(RUNX1):c.508+3delA RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS3 [MET], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP1-Strong [MET], PP3 [MET], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] There is RT-PCR assay evidence demonstrating that the NM_001754.4:c.508+3delA variant creates a cryptic splice donor site that is used and results in a frameshift and introduction of premature termination codon (PS3; PMID: 11830488). This variant was found to co-segregate with disease in multiple affected family members, with eight meioses observed in one family (PP1_Strong; PMID: 11830488). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This intronic variant (in intron 5) is located in reference to the exon at positions +3 for donor splice site and have a predicted decrease in the score of the canonical splice site by at least 75% (measured by both MES and SSF). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PP1_Strong, PM2, PP3, PS4_Supporting. 11830488, 11830488, 11830488, 11830488 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA248618/MONDO:0011071/008 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36171704 14467 G T NM_001754.4(RUNX1):c.861C>A (p.Tyr287Ter) 14467 CA248619 NM_001754.4:c.861C>A, NM_001001890.2:c.780C>A, LRG_482t1:c.861C>A, XM_005261068.3:c.825C>A, XM_005261069.3:c.669C>A, XM_011529766.1:c.861C>A, XM_011529767.1:c.822C>A, XM_011529768.1:c.630C>A, XR_937576.1:n.1040C>A, XM_005261069.4:c.669C>A, XM_011529766.2:c.861C>A, XM_011529767.2:c.822C>A, XM_011529768.2:c.630C>A, XM_017028487.1:c.708C>A, XR_937576.2:n.1087C>A, ENST00000300305.7:c.861C>A, ENST00000344691.8:c.780C>A, ENST00000399240.5:c.588C>A, ENST00000437180.5:c.861C>A, ENST00000482318.5:c.*451C>A, NC_000021.9:g.34799407G>T, CM000683.2:g.34799407G>T, NC_000021.8:g.36171704G>T, CM000683.1:g.36171704G>T, NC_000021.7:g.35093574G>T, NG_011402.2:g.1190305C>A, LRG_482:g.1190305C>A, NM_001754.4(RUNX1):c.861C>A (p.Tyr287Ter) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS3 [Unmet], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP1-Strong [MET], PP3 [Unmet], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [MET] The NM_001754.4:c.861C>A (p.Tyr287Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 11830488). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). The variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PP1_Strong, PM2, PS4_Supporting. 11830488, 11830488, 11830488 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA248619/MONDO:0011071/008 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36252962 14468 C G NM_001754.4(RUNX1):c.400G>C (p.Ala134Pro) 14468 CA248623 NM_001754.4:c.400G>C, NC_000021.9:g.34880665C>G, CM000683.2:g.34880665C>G, NC_000021.8:g.36252962C>G, CM000683.1:g.36252962C>G, NC_000021.7:g.35174832C>G, NG_011402.2:g.1109047G>C, LRG_482:g.1109047G>C, NM_001001890.2:c.319G>C, NM_001122607.1:c.319G>C, LRG_482t1:c.400G>C, XM_005261068.3:c.364G>C, XM_005261069.3:c.400G>C, XM_011529766.1:c.400G>C, XM_011529767.1:c.361G>C, XM_011529768.1:c.361G>C, XM_011529770.1:c.400G>C, XR_937576.1:n.579G>C, XM_005261069.4:c.400G>C, XM_011529766.2:c.400G>C, XM_011529767.2:c.361G>C, XM_011529768.2:c.361G>C, XM_011529770.2:c.400G>C, XM_017028487.1:c.247G>C, XR_937576.2:n.626G>C, ENST00000300305.7:c.400G>C, ENST00000344691.8:c.319G>C, ENST00000358356.9:c.319G>C, ENST00000399237.6:c.364G>C, ENST00000399240.5:c.319G>C, ENST00000437180.5:c.400G>C, ENST00000455571.5:c.361G>C, ENST00000482318.5:c.107G>C, NM_001754.4(RUNX1):c.400G>C (p.Ala134Pro) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [MET], PS1 [Unmet], PS3 [MET], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [MET], PP1 [MET], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] Transactivation assays demonstrate altered transactivation (<20% of wt) for the missense variant, NM_001754.4:c.400G>C (p.Ala134Pro) and data from secondary assays demonstrate altered CBFβ binding and sub-cellular localization.(PS3; PMID: 23848403). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It has a REVEL score >0.75 (0.945) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 12060124). It was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 12060124). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM1, PM2, PP1, PP3, PS4_Supporting. 23848403, 12060124, 12060124, 12060124 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA248623/MONDO:0011071/008 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36259238 14469 G T NM_001754.4(RUNX1):c.253C>A (p.His85Asn) 14469 CA123975 NM_001754.4:c.253C>A, NM_001001890.2:c.172C>A, NM_001122607.1:c.172C>A, LRG_482t1:c.253C>A, XM_005261068.3:c.217C>A, XM_005261069.3:c.253C>A, XM_011529766.1:c.253C>A, XM_011529767.1:c.214C>A, XM_011529768.1:c.214C>A, XM_011529770.1:c.253C>A, XR_937576.1:n.432C>A, XM_005261069.4:c.253C>A, XM_011529766.2:c.253C>A, XM_011529767.2:c.214C>A, XM_011529768.2:c.214C>A, XM_011529770.2:c.253C>A, XM_017028487.1:c.100C>A, XR_937576.2:n.479C>A, ENST00000300305.7:c.253C>A, ENST00000344691.8:c.172C>A, ENST00000358356.9:c.172C>A, ENST00000399237.6:c.217C>A, ENST00000399240.5:c.172C>A, ENST00000437180.5:c.253C>A, ENST00000455571.5:c.214C>A, ENST00000482318.5:c.59-6228C>A, NC_000021.9:g.34886941G>T, CM000683.2:g.34886941G>T, NC_000021.8:g.36259238G>T, CM000683.1:g.36259238G>T, NC_000021.7:g.35181108G>T, NG_011402.2:g.1102771C>A, LRG_482:g.1102771C>A, NM_001754.4(RUNX1):c.253C>A (p.His85Asn) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Benign BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BS3 [MET], BS4 [Unmet], BS1 [MET], PP3 [MET], PP1 [Unmet], PM6 [Unmet], PM2 [Unmet], PVS1 [Unmet] The NM_001754.4:c.253C>A (p.His85Asn) variant has a MAF of 0.00043 (0.043%, 8/18,768 alleles) in the East Asian subpopulation of the gnomAD cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.852) (PP3). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization (BS3; PMID: 23817177, PMID: 10068652). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BS3, PP3. 10068652, 12200707, 10068652, 23817177 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA123975/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 21 36252912 14470 GGCTGCGGT G NM_001754.4(RUNX1):c.442_449delACCGCAGC (p.Thr148Hisfs) 14470 CA248627 NM_001754.4:c.442_449delACCGCAGC, NM_001001890.2:c.361_368del, NM_001122607.1:c.361_368del, NM_001754.4:c.442_449del, LRG_482t1:c.442_449del, XM_005261068.3:c.406_413del, XM_005261069.3:c.442_449del, XM_011529766.1:c.442_449del, XM_011529767.1:c.403_410del, XM_011529768.1:c.403_410del, XM_011529770.1:c.442_449del, XR_937576.1:n.621_628del, XM_005261069.4:c.442_449del, XM_011529766.2:c.442_449del, XM_011529767.2:c.403_410del, XM_011529768.2:c.403_410del, XM_011529770.2:c.442_449del, XM_017028487.1:c.289_296del, XR_937576.2:n.668_675del, ENST00000300305.7:c.442_449del, ENST00000344691.8:c.361_368del, ENST00000358356.9:c.361_368del, ENST00000399237.6:c.406_413del, ENST00000399240.5:c.361_368del, ENST00000437180.5:c.442_449del, ENST00000455571.5:c.403_410del, ENST00000482318.5:c.*32_*39del, NC_000021.9:g.34880616_34880623del, CM000683.2:g.34880616_34880623del, NC_000021.8:g.36252913_36252920del, CM000683.1:g.36252913_36252920del, NC_000021.7:g.35174783_35174790del, NG_011402.2:g.1109089_1109096del, LRG_482:g.1109089_1109096del, NM_001754.4(RUNX1):c.442_449delACCGCAGC (p.Thr148Hisfs) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [MET] The NM_001754.4(RUNX1):c.442_449delACCGCAGC (p.Thr148Hisfs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27112265). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2, PS4_Supporting. 27112265, 27112265, 27112265 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA248627/MONDO:0011071/008 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36252895 14471 G T NM_001754.4(RUNX1):c.467C>A (p.Ala156Glu) 14471 CA248628 NM_001754.4:c.467C>A, NM_001001890.2:c.386C>A, NM_001122607.1:c.386C>A, LRG_482t1:c.467C>A, XM_005261068.3:c.431C>A, XM_005261069.3:c.467C>A, XM_011529766.1:c.467C>A, XM_011529767.1:c.428C>A, XM_011529768.1:c.428C>A, XM_011529770.1:c.467C>A, XR_937576.1:n.646C>A, XM_005261069.4:c.467C>A, XM_011529766.2:c.467C>A, XM_011529767.2:c.428C>A, XM_011529768.2:c.428C>A, XM_011529770.2:c.467C>A, XM_017028487.1:c.314C>A, XR_937576.2:n.693C>A, ENST00000300305.7:c.467C>A, ENST00000344691.8:c.386C>A, ENST00000358356.9:c.386C>A, ENST00000399237.6:c.431C>A, ENST00000399240.5:c.386C>A, ENST00000437180.5:c.467C>A, ENST00000482318.5:c.*57C>A, NC_000021.9:g.34880598G>T, CM000683.2:g.34880598G>T, NC_000021.8:g.36252895G>T, CM000683.1:g.36252895G>T, NC_000021.7:g.35174765G>T, NG_011402.2:g.1109114C>A, LRG_482:g.1109114C>A, NM_001754.4(RUNX1):c.467C>A (p.Ala156Glu) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Pathogenic BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PM1-Supporting [MET], PM5 [Unmet], PM4 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP1-Strong [MET], PP3 [MET], PS4-Supporting [MET], PM6 [Unmet], PM2 [MET], PVS1 [Unmet] The NM_001754.4:c.467C>A (p.Ala156Glu) variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 19357396, 27112265). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This missense variant has a REVEL score >0.75 (0.906) (PP3). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 19357396, 27112265). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_Strong, PM2, PP3, PM1_Supporting, PS4_Supporting. 27112265, 19357396, 27112265, 19357396, 27112265, 19357396 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA248628/MONDO:0011071/008 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763620 17000 A G NM_004004.5(GJB2):c.101T>C (p.Met34Thr) 17000 CA172206 NM_004004.5:c.101T>C, NC_000013.11:g.20189481A>G, CM000675.2:g.20189481A>G, NC_000013.10:g.20763620A>G, CM000675.1:g.20763620A>G, NC_000013.9:g.19661620A>G, NG_008358.1:g.8495T>C, XM_011535049.1:c.101T>C, XM_011535049.2:c.101T>C, NM_004004.6:c.101T>C, ENST00000382844.1:c.101T>C, ENST00000382848.4:c.101T>C, NM_004004.5(GJB2):c.101T>C (p.Met34Thr) GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP1 [MET], PP3 [MET], PP4 [Unmet], PM3-Very Strong [MET], BP2 [Unmet], BP4 [Unmet], BP3 [Unmet], BA1 [Unmet], PS4 [MET], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PM5 [Unmet], PM1 [Unmet], PM4 [Unmet], BP7 [Unmet], BP5 [Unmet], BS4 [Unmet], BS1 [Unmet] The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for European (non-Finnish) genomes in gnomAD. This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 27 homozygous affected probands, 17 affected probands with the p.Val37Ile variant in trans, 138 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans (PM3; PMID 31160754). The REVEL computational prediction analysis tool produced a score of 0.702, which is above the threshold necessary to apply PP3. Most dye transfer and electrical coupling assays support that the variant impacts protein function (PMID: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493); however, some assays showed partial function (PMID: 27884957), and therefore this evidence was not counted. At least 16 segregations of the p.Met34Thr variant in family members have been described (PP1_Strong, PMID: 31160754, 10903123). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Met34Thr in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing lossbased on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3, PP3. 31160754, 31160754, 10903123, 31160754, 14694360, 31160754, 31160754, 31160754, 31160754, 15033936, 27884957, 16300957, 10556284, 12189493, 16849369, 10903123, 31160754, 14694360, 31160754 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA172206/MONDO:0019497/005 0.1 VUS Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 13 20763650 17002 C T NM_004004.5(GJB2):c.71G>A (p.Trp24Ter) 17002 CA172240 NM_004004.5:c.71G>A, XM_011535049.1:c.71G>A, XM_011535049.2:c.71G>A, NM_004004.6:c.71G>A, ENST00000382844.1:c.71G>A, ENST00000382848.4:c.71G>A, NC_000013.11:g.20189511C>T, CM000675.2:g.20189511C>T, NC_000013.10:g.20763650C>T, CM000675.1:g.20763650C>T, NC_000013.9:g.19661650C>T, NG_008358.1:g.8465G>A, NM_004004.5(GJB2):c.71G>A (p.Trp24Ter) GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PM6 [Unmet], PVS1 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], PM3-Very Strong [MET], BP2 [Unmet], BP4 [Unmet], BP3 [Unmet], BA1 [Unmet], PS3 [MET], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [MET], BS4 [Unmet] The filtering allele frequency of the p.Trp24X variant in the GJB2 gene is 0.38% (137/ 30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). However, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BS1 code will not contribute to the overall classification. The p.Trp24X variant in GJB2 is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 15070423, 24123366, 18941476, 9139825). A knock-in mouse model demonstrates that the p.Trp24X variant leads to the phenotype (PS3; PMID:18941476). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS3, BS1. 9139825, 18941476, 24123366, 15070423, 9139825, 18941476, 24123366, 15070423, 18941476 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-17 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA172240/MONDO:0019497/005 0.9986 Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763685 17004 AC A NM_004004.5(GJB2):c.35delG (p.Gly12Valfs) 17004 CA127023 NM_004004.5:c.35del, NM_004004.5:c.35delG, NC_000013.11:g.20189552del, CM000675.2:g.20189552del, NC_000013.10:g.20763691del, CM000675.1:g.20763691del, NC_000013.9:g.19661691del, NG_008358.1:g.8429del, XM_011535049.1:c.35del, XM_011535049.2:c.35del, NM_004004.6:c.35del, ENST00000382844.1:c.35del, ENST00000382848.4:c.35del, NM_004004.5(GJB2):c.35delG (p.Gly12Valfs) GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PM6 [Unmet], PVS1 [MET], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], PM3-Very Strong [MET], BP2 [Unmet], BP4 [Unmet], BP3 [Unmet], BA1 [MET], PS4 [MET], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The c.35delG variant in GJB2 is predicted to cause a premature stop codon in biologically-relevant-exon 2/2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 26445815). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 26969326, 25999548). The filtering allele frequency of the c.35delG variant in the GJB2 gene is 0.9% for European (Non-Finnish) chromosomes in the Genome Aggregation Database (1207/124552 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS4, BA1. 26969326, 25999548 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-20 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA127023/MONDO:0019497/005 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763485 17014 AG A NM_004004.5(GJB2):c.235delC (p.Leu79Cysfs) 17014 CA127025 NM_004004.5:c.235del, NM_004004.5:c.235delC, XM_011535049.1:c.235del, XM_011535049.2:c.235del, NM_004004.6:c.235del, ENST00000382844.1:c.235del, ENST00000382848.4:c.235del, NC_000013.11:g.20189349del, CM000675.2:g.20189349del, NC_000013.10:g.20763488del, CM000675.1:g.20763488del, NC_000013.9:g.19661488del, NG_008358.1:g.8629del, NM_004004.5(GJB2):c.235delC (p.Leu79Cysfs) GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PVS1 [MET], PP3 [Unmet], PS3-Moderate [MET], PM3-Very Strong [MET], BA1 [Unmet], BS1 [MET] The filtering allele frequency of the p.Leu79CysfsX3 variant in the GJB2 gene is 0.55% (121/ 18870) of East Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BS1 code will not contribute to the overall classification. The p.Leu79CysfsX3 variant in GJB2 is predicted to cause a premature stop codon in the only exon of the gene, leading to absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 10983956, 10633133). A dye transfer assay, a functional study, has shown that the variant impacts protein function (PS3_M; PMID: 12352684). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS3_M, BS1. 12352684, 10983956, 10633133 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA127025/MONDO:0019497/005 0.9492 Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68845762 18453 G T NM_004360.4(CDH1):c.1008G>T (p.Glu336Asp) 18453 CA280990 NM_004360.4:c.1008G>T, NM_004360.3:c.1008G>T, LRG_301t1:c.1008G>T, XM_011523488.1:c.273G>T, XM_011523489.1:c.273G>T, NM_001317184.1:c.1008G>T, NM_001317185.1:c.-608G>T, NM_001317186.1:c.-812G>T, ENST00000261769.9:c.1008G>T, ENST00000422392.6:c.1008G>T, ENST00000561751.1:n.630G>T, ENST00000562836.5:n.1079G>T, ENST00000566510.5:c.852G>T, ENST00000566612.5:c.1008G>T, ENST00000611625.4:c.1008G>T, ENST00000612417.4:c.1008G>T, ENST00000621016.4:c.1008G>T, NC_000016.10:g.68811859G>T, CM000678.2:g.68811859G>T, NC_000016.9:g.68845762G>T, CM000678.1:g.68845762G>T, NC_000016.8:g.67403263G>T, NG_008021.1:g.79568G>T, LRG_301:g.79568G>T, NM_004360.4(CDH1):c.1008G>T (p.Glu336Asp) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Likely Pathogenic BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PS4-Supporting [MET], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [MET], PS1 [Unmet], PS2 [Unmet], PVS1-Moderate [MET] The c.1008G>T (p.Glu336Asp) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 9537325). Additionally, the variant has also been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 9537325). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Moderate, PM2, PS3, PS4_Supporting. 9537325 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA280990/MONDO:0007648/007 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763382 21385 A C NM_004004.5(GJB2):c.339T>G (p.Ser113Arg) 21385 CA342004 NM_004004.5:c.339T>G, XM_011535049.1:c.339T>G, XM_011535049.2:c.339T>G, NM_004004.6:c.339T>G, ENST00000382844.1:c.339T>G, ENST00000382848.4:c.339T>G, NC_000013.11:g.20189243A>C, CM000675.2:g.20189243A>C, NC_000013.10:g.20763382A>C, CM000675.1:g.20763382A>C, NC_000013.9:g.19661382A>C, NG_008358.1:g.8733T>G, NM_004004.5(GJB2):c.339T>G (p.Ser113Arg) GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Uncertain Significance PP3 [Unmet], PS3-Moderate [MET], PM2-Supporting [MET], BP4 [Unmet], PM3 [MET] The allele frequency of the c.339T>G (p.Ser113Arg) variant in the GJB2 gene is 0.02% (3/10064) of Ashkenazi Jewish chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.55, which does not meet the threshold necessary to apply PP3 or BP4. An in vitro functional study performed in Xenopus oocytes showed that variant junctional conductance for p.Ser113Arg was similar to water (negative control), indicating a loss of function impact on protein function (PS3_Moderate; PMID:12505163). The p.Ser113Arg variant has been reported in at least 5 probands with hearing loss, and 2 individuals were compound heterozygous for a pathogenic variant without phase confirmation (PM3, PMID: 15365987, 11439000, 9529365, 16380907, 23826813). In summary, although there is some evidence for pathogenicity the clinical significance of this variant is currently uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : PS3_Moderate, PM3, PM2_Supporting. 12505163, 9529365, 16380907, 11439000, 15365987, 24078562 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA342004/MONDO:0019497/005 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 0, 0] 1 Uncertain Significance 10 89711882 39668 C A NM_000314.6(PTEN):c.500C>A (p.Thr167Asn) 39668 CA000487 NM_000314.6:c.500C>A, NM_000314.5:c.500C>A, NM_001304717.2:c.1019C>A, NM_001304718.1:c.-92C>A, XM_006717926.2:c.455C>A, XM_011539981.1:c.500C>A, XM_011539982.1:c.404C>A, XR_945789.1:n.1371C>A, XR_945790.1:n.1488C>A, XR_945791.1:n.1205-5728C>A, NM_000314.7:c.500C>A, NM_001304717.5:c.1019C>A, NM_001304718.2:c.-92C>A, ENST00000371953.7:c.500C>A, NC_000010.11:g.87952125C>A, CM000672.2:g.87952125C>A, NC_000010.10:g.89711882C>A, CM000672.1:g.89711882C>A, NC_000010.9:g.89701862C>A, NG_007466.2:g.93687C>A, LRG_311:g.93687C>A, NM_000314.6(PTEN):c.500C>A (p.Thr167Asn) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PVS1 [Unmet], PM2 [MET], PM6 [MET], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PS4 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [MET] PTEN c.500C>A (p.Thr167Asn) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 23160955)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 28250423, 23160955, 28250423, 23160955, 23160955 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-11-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000487/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 10 89692908 39669 C T NM_000314.6(PTEN):c.392C>T (p.Thr131Ile) 39669 CA000442 NM_000314.6:c.392C>T, NM_000314.5:c.392C>T, NM_001304717.2:c.911C>T, NM_001304718.1:c.-359C>T, XM_006717926.2:c.347C>T, XM_011539981.1:c.392C>T, XM_011539982.1:c.296C>T, XR_945789.1:n.1104C>T, XR_945790.1:n.1104C>T, XR_945791.1:n.1104C>T, NM_000314.7:c.392C>T, NM_001304717.5:c.911C>T, NM_001304718.2:c.-359C>T, ENST00000371953.7:c.392C>T, ENST00000498703.1:n.218C>T, ENST00000610634.1:c.290C>T, NC_000010.11:g.87933151C>T, CM000672.2:g.87933151C>T, NC_000010.10:g.89692908C>T, CM000672.1:g.89692908C>T, NC_000010.9:g.89682888C>T, NG_007466.2:g.74713C>T, LRG_311:g.74713C>T, NM_000314.6(PTEN):c.392C>T (p.Thr131Ile) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PVS1 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP4 [Unmet], PP1 [Unmet], PM6-Strong [MET], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS4-Moderate [MET], PS1 [Unmet], PS2 [Unmet], PS3 [MET], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.392C>T (p.Thr131Ile) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 21828076)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (PMID 23160955, 23335809 author communication)PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 23160955, 23335809)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 23335809, 23160955, 23335809, 28250423, 23160955, 23335809, 23160955, 23335809, 28250423, 29785012, 21828076, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-11-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000442/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 7 140624468 40333 C T NM_004333.4(BRAF):c.36G>A (p.Ala12=) 40333 CA281921 NM_004333.4:c.36G>A, LRG_299t1:c.36G>A, XM_005250045.1:c.36G>A, XM_005250046.1:c.36G>A, XM_011516529.1:c.36G>A, XM_011516530.1:c.36G>A, XR_242190.1:n.44G>A, XR_927520.1:n.44G>A, XR_927521.1:n.44G>A, XR_927522.1:n.44G>A, XR_927523.1:n.44G>A, NM_001354609.1:c.36G>A, NM_004333.5:c.36G>A, NR_148928.1:n.261G>A, XM_017012558.1:c.36G>A, XM_017012559.1:c.36G>A, XR_001744857.1:n.44G>A, XR_001744858.1:n.44G>A, ENST00000288602.10:c.36G>A, ENST00000469930.1:n.42G>A, NC_000007.14:g.140924668C>T, CM000669.2:g.140924668C>T, NC_000007.13:g.140624468C>T, CM000669.1:g.140624468C>T, NC_000007.12:g.140270937C>T, NG_007873.3:g.5097G>A, LRG_299:g.5097G>A, NM_004333.4(BRAF):c.36G>A (p.Ala12=) BRAF RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.36G>A (p.Ala12=) variant in the BRAF gene is 0.116% (14/7290) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA281921/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 11 534242 40431 A G NM_005343.3(HRAS):c.81T>C (p.His27=) 40431 CA135996 NM_005343.3:c.81T>C, NC_000011.10:g.534242A>G, CM000673.2:g.534242A>G, NC_000011.9:g.534242A>G, CM000673.1:g.534242A>G, NC_000011.8:g.524242A>G, NG_007666.1:g.6309T>C, NM_001130442.1:c.81T>C, NM_005343.2:c.81T>C, NM_176795.3:c.81T>C, XM_011519875.1:c.-424-4356A>G, XM_011519877.1:c.-161-5338A>G, XR_242795.1:n.280T>C, NM_001130442.2:c.81T>C, NM_001318054.1:c.-239T>C, NM_176795.4:c.81T>C, XM_011519875.2:c.-424-4356A>G, XM_011519877.2:c.-161-5338A>G, XM_017017167.1:c.-499-4281A>G, XM_017017168.1:c.-499-4281A>G, NM_005343.4:c.81T>C, ENST00000311189.7:c.81T>C, ENST00000397594.5:c.81T>C, ENST00000397596.6:c.81T>C, ENST00000417302.5:c.81T>C, ENST00000451590.5:c.81T>C, ENST00000468682.2:n.569T>C, ENST00000493230.5:c.81T>C, NM_005343.3(HRAS):c.81T>C (p.His27=) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.81T>C (p.His27=) variant in the HRAS gene is 36.7% for African chromosomes by the Exome Aggregation Consortium (3874/10274 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additional case-level data provided by: SCV000058315; SCV000062146; SCV000196686. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA135996/MONDO:0021060/004 0 Benign auto Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=1 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 11 533881 40435 C T NM_005343.3(HRAS):c.175G>A (p.Ala59Thr) 40435 CA176353 NM_005343.3:c.175G>A, NC_000011.10:g.533881C>T, CM000673.2:g.533881C>T, NC_000011.9:g.533881C>T, CM000673.1:g.533881C>T, NC_000011.8:g.523881C>T, NG_007666.1:g.6670G>A, NM_001130442.1:c.175G>A, NM_005343.2:c.175G>A, NM_176795.3:c.175G>A, XM_011519875.1:c.-424-4717C>T, XM_011519877.1:c.-162+5544C>T, XR_242795.1:n.374G>A, NM_001130442.2:c.175G>A, NM_001318054.1:c.-145G>A, NM_176795.4:c.175G>A, XM_011519875.2:c.-424-4717C>T, XM_011519877.2:c.-162+5544C>T, XM_017017167.1:c.-499-4642C>T, XM_017017168.1:c.-499-4642C>T, NM_005343.4:c.175G>A, ENST00000311189.7:c.175G>A, ENST00000397594.5:c.175G>A, ENST00000397596.6:c.175G>A, ENST00000417302.5:c.175G>A, ENST00000451590.5:c.175G>A, ENST00000468682.2:n.663G>A, ENST00000479482.1:n.96G>A, ENST00000493230.5:c.175G>A, NM_005343.3(HRAS):c.175G>A (p.Ala59Thr) LRRC56 Costello syndrome MONDO:0009026 Autosomal dominant inheritance Likely Pathogenic PP1 [MET], PP3 [MET], PP2 [MET], PS4-Supporting [MET], PM1 [MET], PM2 [MET] The c.175G>A (p.Ala59Thr) variant has been identified in at least 2 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Partners LMM internal data; GTR ID's: 26957, 21766; ClinVar SCV000198374; SCV000207851). The p.Ala59Thr variant in HRAS has been reported in the literature to segregate with clinical features of a RASopathy in at least 3 family members (PP1; SCV000198374). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Ala59Thr variant may impact the protein (PP3). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP1, PP2, PP3, PS4_Supporting, PM1, PM2. 29493581 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA176353/MONDO:0009026/004 0.9941 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 11 533799 40437 T G NM_005343.3(HRAS):c.257A>C (p.Asn86Thr) 40437 CA180888 NM_005343.3:c.257A>C, NM_001130442.1:c.257A>C, NM_005343.2:c.257A>C, NM_176795.3:c.257A>C, XM_011519875.1:c.-424-4799T>G, XM_011519877.1:c.-162+5462T>G, XR_242795.1:n.456A>C, NM_001130442.2:c.257A>C, NM_001318054.1:c.-63A>C, NM_176795.4:c.257A>C, XM_011519875.2:c.-424-4799T>G, XM_011519877.2:c.-162+5462T>G, XM_017017167.1:c.-499-4724T>G, XM_017017168.1:c.-499-4724T>G, NM_005343.4:c.257A>C, ENST00000311189.7:c.257A>C, ENST00000397594.5:c.257A>C, ENST00000397596.6:c.257A>C, ENST00000417302.5:c.257A>C, ENST00000451590.5:c.257A>C, ENST00000468682.2:n.745A>C, ENST00000479482.1:n.178A>C, ENST00000493230.5:c.257A>C, NC_000011.10:g.533799T>G, CM000673.2:g.533799T>G, NC_000011.9:g.533799T>G, CM000673.1:g.533799T>G, NC_000011.8:g.523799T>G, NG_007666.1:g.6752A>C, NM_005343.3(HRAS):c.257A>C (p.Asn86Thr) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BP5 [MET], BA1 [MET] The filtering allele frequency of the c.257A>C (p.Asn86Thr) variant in the HRAS gene is 0.07% for African chromosomes by the Exome Aggregation Consortium (12/10342 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM, GeneDx internal data GTR ID: 21766, 26957 ClinVar SCV000204177.4; SCV000207861.7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied: BA1, BP5. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA180888/MONDO:0021060/004 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 11 533779 40439 T C NM_176795.4(HRAS):c.277A>G (p.Ile93Val) 40439 CA296061 NM_176795.4:c.277A>G, NM_001130442.1:c.277A>G, NM_005343.2:c.277A>G, NM_176795.3:c.277A>G, XM_011519875.1:c.-424-4819T>C, XM_011519877.1:c.-162+5442T>C, XR_242795.1:n.476A>G, NM_001130442.2:c.277A>G, NM_001318054.1:c.-43A>G, NM_005343.3:c.277A>G, XM_011519875.2:c.-424-4819T>C, XM_011519877.2:c.-162+5442T>C, XM_017017167.1:c.-499-4744T>C, XM_017017168.1:c.-499-4744T>C, NM_005343.4:c.277A>G, ENST00000311189.7:c.277A>G, ENST00000397594.5:c.277A>G, ENST00000397596.6:c.277A>G, ENST00000417302.5:c.277A>G, ENST00000451590.5:c.277A>G, ENST00000479482.1:n.198A>G, ENST00000493230.5:c.277A>G, NC_000011.10:g.533779T>C, CM000673.2:g.533779T>C, NC_000011.9:g.533779T>C, CM000673.1:g.533779T>C, NC_000011.8:g.523779T>C, NG_007666.1:g.6772A>G, NM_176795.4(HRAS):c.277A>G (p.Ile93Val) LRRC56 Costello syndrome MONDO:0009026 Autosomal dominant inheritance Uncertain Significance PS4-Supporting [MET], PM2 [MET] The c.277A>G (p.Ile93Val) variant has been identified in at least 2 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Blueprint genetics internal data; GTR ID's: 26957, 500188 ClinVar SCV000207855; SCV000188770). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In summary, the clinical significance of the p.Ile93Val variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA296061/MONDO:0009026/004 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 11 533594 40440 C T NM_005343.3(HRAS):c.309G>A (p.Val103=) 40440 CA5779334 NM_005343.3:c.309G>A, NC_000011.10:g.533594C>T, CM000673.2:g.533594C>T, NC_000011.9:g.533594C>T, CM000673.1:g.533594C>T, NC_000011.8:g.523594C>T, NG_007666.1:g.6957G>A, NM_001130442.1:c.309G>A, NM_005343.2:c.309G>A, NM_176795.3:c.309G>A, XM_011519875.1:c.-424-5004C>T, XM_011519877.1:c.-162+5257C>T, XR_242795.1:n.508G>A, NM_001130442.2:c.309G>A, NM_001318054.1:c.-11G>A, NM_176795.4:c.309G>A, XM_011519875.2:c.-424-5004C>T, XM_011519877.2:c.-162+5257C>T, XM_017017167.1:c.-499-4929C>T, XM_017017168.1:c.-499-4929C>T, NM_005343.4:c.309G>A, ENST00000311189.7:c.309G>A, ENST00000397594.5:c.309G>A, ENST00000397596.6:c.309G>A, ENST00000417302.5:c.309G>A, ENST00000451590.5:c.309G>A, ENST00000462734.1:n.2G>A, ENST00000478324.5:n.19G>A, ENST00000479482.1:n.230G>A, ENST00000493230.5:c.309G>A, NM_005343.3(HRAS):c.309G>A (p.Val103=) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.309G>A (p.Val103=) variant in the HRAS gene is 0.063% (10/8640) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA5779334/MONDO:0021060/004 0.025 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 11 533546 40441 G A NM_005343.3(HRAS):c.357C>T (p.Asp119=) 40441 CA135978 NM_005343.3:c.357C>T, NM_001130442.1:c.357C>T, NM_005343.2:c.357C>T, NM_176795.3:c.357C>T, XM_011519875.1:c.-424-5052G>A, XM_011519877.1:c.-162+5209G>A, XR_242795.1:n.556C>T, NM_001130442.2:c.357C>T, NM_001318054.1:c.38C>T, NM_176795.4:c.357C>T, XM_011519875.2:c.-424-5052G>A, XM_011519877.2:c.-162+5209G>A, XM_017017167.1:c.-499-4977G>A, XM_017017168.1:c.-499-4977G>A, NM_005343.4:c.357C>T, ENST00000311189.7:c.357C>T, ENST00000397594.5:c.357C>T, ENST00000397596.6:c.357C>T, ENST00000417302.5:c.357C>T, ENST00000451590.5:c.357C>T, ENST00000462734.1:n.50C>T, ENST00000478324.5:n.67C>T, ENST00000479482.1:n.278C>T, ENST00000493230.5:c.357C>T, NC_000011.10:g.533546G>A, CM000673.2:g.533546G>A, NC_000011.9:g.533546G>A, CM000673.1:g.533546G>A, NC_000011.8:g.523546G>A, NG_007666.1:g.7005C>T, NM_005343.3(HRAS):c.357C>T (p.Asp119=) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.357C>T (p.Asp119=) variant in the HRAS gene is 0.129% (102/66416) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA135978/MONDO:0021060/004 0.025 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 11 533525 40442 T C NM_005343.3(HRAS):c.378A>G (p.Glu126=) 40442 CA135984 NM_005343.3:c.378A>G, NM_001130442.1:c.378A>G, NM_005343.2:c.378A>G, NM_176795.3:c.378A>G, XM_011519875.1:c.-424-5073T>C, XM_011519877.1:c.-162+5188T>C, XR_242795.1:n.577A>G, NM_001130442.2:c.378A>G, NM_001318054.1:c.59A>G, NM_176795.4:c.378A>G, XM_011519875.2:c.-424-5073T>C, XM_011519877.2:c.-162+5188T>C, XM_017017167.1:c.-499-4998T>C, XM_017017168.1:c.-499-4998T>C, NM_005343.4:c.378A>G, ENST00000311189.7:c.378A>G, ENST00000397594.5:c.378A>G, ENST00000397596.6:c.378A>G, ENST00000417302.5:c.378A>G, ENST00000451590.5:c.378A>G, ENST00000462734.1:n.71A>G, ENST00000478324.5:n.88A>G, ENST00000479482.1:n.299A>G, ENST00000493230.5:c.378A>G, NC_000011.10:g.533525T>C, CM000673.2:g.533525T>C, NC_000011.9:g.533525T>C, CM000673.1:g.533525T>C, NC_000011.8:g.523525T>C, NG_007666.1:g.7026A>G, NM_005343.3(HRAS):c.378A>G (p.Glu126=) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.378A>G (p.Glu126=) variant in the HRAS gene is 0.095% (23/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA135984/MONDO:0021060/004 0.025 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 11 532729 40446 C T NM_005343.3(HRAS):c.477G>A (p.Leu159=) 40446 CA135990 NM_005343.3:c.477G>A, NC_000011.10:g.532729C>T, CM000673.2:g.532729C>T, NC_000011.9:g.532729C>T, CM000673.1:g.532729C>T, NC_000011.8:g.522729C>T, NG_007666.1:g.7822G>A, NM_001130442.1:c.477G>A, NM_005343.2:c.477G>A, NM_176795.3:c.*46G>A, XM_011519875.1:c.-425+4392C>T, XM_011519877.1:c.-162+4392C>T, XR_242795.1:n.758G>A, NM_001130442.2:c.477G>A, NM_001318054.1:c.240G>A, NM_176795.4:c.*46G>A, XM_011519875.2:c.-425+4392C>T, XM_011519877.2:c.-162+4392C>T, XM_017017167.1:c.-500+4392C>T, XM_017017168.1:c.-500+4392C>T, NM_005343.4:c.477G>A, ENST00000311189.7:c.477G>A, ENST00000397594.5:c.*46G>A, ENST00000397596.6:c.477G>A, ENST00000417302.5:c.*46G>A, ENST00000451590.5:c.477G>A, ENST00000462734.1:n.252G>A, ENST00000478324.5:n.243-99G>A, ENST00000479482.1:n.398G>A, ENST00000493230.5:c.*46G>A, NM_005343.3(HRAS):c.477G>A (p.Leu159=) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.477G>A (p.Leu159=) variant in the HRAS gene is 0.185% (140/65296) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA135990/MONDO:0021060/004 0.025 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 11 532698 40447 T A NM_005343.3(HRAS):c.508A>T (p.Lys170Ter) 40447 CA296052 NM_005343.3:c.508A>T, NC_000011.10:g.532698T>A, CM000673.2:g.532698T>A, NC_000011.9:g.532698T>A, CM000673.1:g.532698T>A, NC_000011.8:g.522698T>A, NG_007666.1:g.7853A>T, NM_001130442.1:c.508A>T, NM_005343.2:c.508A>T, NM_176795.3:c.*77A>T, XM_011519875.1:c.-425+4361T>A, XM_011519877.1:c.-162+4361T>A, XR_242795.1:n.789A>T, NM_001130442.2:c.508A>T, NM_001318054.1:c.271A>T, NM_176795.4:c.*77A>T, XM_011519875.2:c.-425+4361T>A, XM_011519877.2:c.-162+4361T>A, XM_017017167.1:c.-500+4361T>A, XM_017017168.1:c.-500+4361T>A, NM_005343.4:c.508A>T, ENST00000311189.7:c.508A>T, ENST00000397594.5:c.*77A>T, ENST00000397596.6:c.508A>T, ENST00000417302.5:c.*77A>T, ENST00000451590.5:c.508A>T, ENST00000462734.1:n.283A>T, ENST00000478324.5:n.243-68A>T, ENST00000479482.1:n.429A>T, ENST00000493230.5:c.*77A>T, NM_005343.3(HRAS):c.508A>T (p.Lys170Ter) HRAS Costello syndrome MONDO:0009026 Autosomal dominant inheritance Uncertain Significance BS2 [Unmet], PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS2 [Unmet], PS4 [Unmet], PS3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [MET], BS3 [Unmet], PM2 [Unmet], PM6 [Unmet], BP1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet] The c.508A>T (p.Lys170Ter) variant in the HRAS gene has been identified in patients with cancer and individuals who underwent testing for RASopathies, however it was also identified in an unaffected parent (BS4; Invitae, GeneDx internal data, GTR Lab ID: 26957, 500031; SCV000207840.14, SCV000635092.3). The filtering allele frequency of the p.Lys170Ter variant is 0.0034% for European (non-Finnish) chromosomes by the gnomAD aggregation database (8/249358 with 95% CI), which is not a high enough frequency to meet thresholds defined by the ClinGen RASopahty Expert panel for autosomal dominant RASopathy variants (BA1/BS1 not met). Furthermore, LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore the PVS1 rule is not applicable. In summary, the clinical significance of the p.Lys170Ter variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false 0.9986 Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 11 532686 40448 G A NM_005343.3(HRAS):c.520C>T (p.Pro174Ser) 40448 CA135994 NM_005343.3:c.520C>T, NM_001130442.1:c.520C>T, NM_005343.2:c.520C>T, NM_176795.3:c.*89C>T, XM_011519875.1:c.-425+4349G>A, XM_011519877.1:c.-162+4349G>A, XR_242795.1:n.801C>T, NM_001130442.2:c.520C>T, NM_001318054.1:c.283C>T, NM_176795.4:c.*89C>T, XM_011519875.2:c.-425+4349G>A, XM_011519877.2:c.-162+4349G>A, XM_017017167.1:c.-500+4349G>A, XM_017017168.1:c.-500+4349G>A, NM_005343.4:c.520C>T, ENST00000311189.7:c.520C>T, ENST00000397594.5:c.*89C>T, ENST00000397596.6:c.520C>T, ENST00000417302.5:c.*89C>T, ENST00000451590.5:c.520C>T, ENST00000462734.1:n.295C>T, ENST00000478324.5:n.243-56C>T, ENST00000479482.1:n.441C>T, ENST00000493230.5:c.*89C>T, NC_000011.10:g.532686G>A, CM000673.2:g.532686G>A, NC_000011.9:g.532686G>A, CM000673.1:g.532686G>A, NC_000011.8:g.522686G>A, NG_007666.1:g.7865C>T, NM_005343.3(HRAS):c.520C>T (p.Pro174Ser) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.520C>T (p.Pro174Ser) variant in the HRAS gene is 0.115% (20/11482) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA135994/MONDO:0021060/004 0.025 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 12 112888228 40504 A G NM_002834.4(PTPN11):c.244A>G (p.Met82Val) 40504 CA243279 NM_002834.4:c.244A>G, NC_000012.12:g.112450424A>G, CM000674.2:g.112450424A>G, NC_000012.11:g.112888228A>G, CM000674.1:g.112888228A>G, NC_000012.10:g.111372611A>G, NG_007459.1:g.36693A>G, LRG_614:g.36693A>G, NM_002834.3:c.244A>G, LRG_614t1:c.244A>G, NM_080601.1:c.244A>G, XM_006719526.1:c.244A>G, XM_006719527.1:c.244A>G, XM_011538613.1:c.241A>G, NM_001330437.1:c.244A>G, NM_080601.2:c.244A>G, XM_011538613.2:c.241A>G, XM_017019722.1:c.241A>G, ENST00000351677.6:c.244A>G, ENST00000392597.5:c.244A>G, ENST00000635625.1:n.244A>G, NM_002834.4(PTPN11):c.244A>G (p.Met82Val) PTPN11 RASopathy MONDO:0021060 Autosomal dominant inheritance Uncertain Significance PP2 [MET], BP5 [MET] The c.244A>G p.Met82Val variant in PTPN11 has been identified in patients with clinical features of a RASopathy (PS4 not met; GeneDx, EGL genetics internal data; GTR ID's: 26957, 500060; SCV000057386.11; SCV000228999.4). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data; GTR ID's: 26957; SCV000057386.11). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). In summary, the clinical significance of the p.Met82Val variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP5, PP2. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA243279/MONDO:0021060/004 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 112915779 40541 G A NM_002834.4(PTPN11):c.1052G>A (p.Arg351Gln) 40541 CA282114 NM_002834.4:c.1052G>A, NC_000012.12:g.112477975G>A, CM000674.2:g.112477975G>A, NC_000012.11:g.112915779G>A, CM000674.1:g.112915779G>A, NC_000012.10:g.111400162G>A, NG_007459.1:g.64244G>A, LRG_614:g.64244G>A, NM_002834.3:c.1052G>A, LRG_614t1:c.1052G>A, NM_080601.1:c.1052G>A, XM_006719526.1:c.1052G>A, XM_006719527.1:c.938G>A, XM_011538613.1:c.1049G>A, NM_001330437.1:c.1052G>A, NM_080601.2:c.1052G>A, XM_011538613.2:c.1049G>A, XM_017019722.1:c.1049G>A, ENST00000351677.6:c.1052G>A, ENST00000392597.5:c.1052G>A, ENST00000635625.1:n.1052G>A, ENST00000635652.1:n.44G>A, NM_002834.4(PTPN11):c.1052G>A (p.Arg351Gln) PTPN11 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1052G>A (p.Arg351Gln) variant in the PTPN11 gene is 0.263% (55/16488) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA282114/MONDO:0021060/004 0.0507 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 112926910 40567 G C NM_002834.4(PTPN11):c.1530G>C (p.Gln510His) 40567 CA220143 NM_002834.4:c.1530G>C, NC_000012.12:g.112489106G>C, CM000674.2:g.112489106G>C, NC_000012.11:g.112926910G>C, CM000674.1:g.112926910G>C, NC_000012.10:g.111411293G>C, NG_007459.1:g.75375G>C, LRG_614:g.75375G>C, NM_002834.3:c.1530G>C, LRG_614t1:c.1530G>C, XM_006719526.1:c.1542G>C, XM_006719527.1:c.1428G>C, XM_011538613.1:c.1539G>C, NM_001330437.1:c.1542G>C, XM_011538613.2:c.1539G>C, XM_017019722.1:c.1527G>C, ENST00000351677.6:c.1530G>C, ENST00000635625.1:n.1542G>C, ENST00000635652.1:n.543G>C, NM_002834.4(PTPN11):c.1530G>C (p.Gln510His) PTPN11 RASopathy MONDO:0021060 Autosomal dominant inheritance Pathogenic PP3 [MET], PP2 [MET], PM6-Strong [MET], PM5-Strong [MET], PM2 [MET] The c.1530G>C (p.Gln510His) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, EGL, APHP-Robert Debré Hospital internal data; GTR ID's: 26957, 500060, 28338 ClinVar SCV000057460.11; SCV000331072.3). At least 2 other pathogenic missense variants have been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40566, 13345, 13344). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln510His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM5_Strong, PM2, PP3, PP2. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220143/MONDO:0021060/004 0.9941 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 3 12660127 40584 T C NM_002880.3(RAF1):c.94A>G (p.Ile32Val) 40584 CA241481 NM_002880.3:c.94A>G, NC_000003.12:g.12618628T>C, CM000665.2:g.12618628T>C, NC_000003.11:g.12660127T>C, CM000665.1:g.12660127T>C, NC_000003.10:g.12635127T>C, NG_007467.1:g.50552A>G, LRG_413:g.50552A>G, LRG_413t1:c.94A>G, XM_005265355.1:c.94A>G, XM_005265357.1:c.94A>G, XM_005265358.3:c.-37A>G, XM_005265359.3:c.-37A>G, XM_005265360.1:c.94A>G, XM_011533974.1:c.94A>G, XM_011533975.1:c.-37A>G, NM_001354689.1:c.94A>G, NM_001354690.1:c.94A>G, NM_001354691.1:c.-37A>G, NM_001354692.1:c.-37A>G, NM_001354693.1:c.94A>G, NM_001354694.1:c.-37A>G, NM_001354695.1:c.-37A>G, NR_148940.1:n.509A>G, NR_148941.1:n.509A>G, NR_148942.1:n.509A>G, XM_011533974.3:c.94A>G, XM_017006966.1:c.94A>G, XR_001740227.1:n.425A>G, ENST00000251849.8:c.94A>G, ENST00000416093.1:c.94A>G, ENST00000423275.5:c.94A>G, ENST00000442415.6:c.94A>G, NM_002880.3(RAF1):c.94A>G (p.Ile32Val) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BS2 [MET], PP1 [Unmet], PP2 [MET], PP3 [Unmet], PM4 [Unmet], PM1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], BP7 [Unmet], BP5 [MET], BS1 [MET], BS4 [Unmet], BS3 [Unmet], PM2 [Unmet], PM6 [Unmet], BP1 [Unmet], BP4 [MET], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet] The c.94A>G (p.Ile32Val) variant in the RAF1 gene has been identified in patients who underwent testing for a RASopathy, however it has also been identified in multiple adults who did not have clinical features of a RASopathy (BS2, BP5; Invitae, EGL Diagnostics, GeneDx internal data; GTR Lab ID: 500031, 500060; SCV000287747.4, SCV000227277.5, SCV000209002.14). The filtering allele frequency of the p.Ile32Val variant is 0.017% for European (non-Finnish) genomes in the gnomAD database (8/31404 with 95% CI) which is a high enough frequency to be considered strong evidence that the variant is benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1). Computational prediction tools and conservation analysis suggest that the p.Ile32Val variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS2, BP5, BS1, BP4. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA241481/MONDO:0021060/004 0.1 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 3 12660102 40585 C T NM_002880.3(RAF1):c.119G>A (p.Arg40His) 40585 CA201617 NM_002880.3:c.119G>A, LRG_413t1:c.119G>A, XM_005265355.1:c.119G>A, XM_005265357.1:c.119G>A, XM_005265358.3:c.-12G>A, XM_005265359.3:c.-12G>A, XM_005265360.1:c.119G>A, XM_011533974.1:c.119G>A, XM_011533975.1:c.-12G>A, NM_001354689.1:c.119G>A, NM_001354690.1:c.119G>A, NM_001354691.1:c.-12G>A, NM_001354692.1:c.-12G>A, NM_001354693.1:c.119G>A, NM_001354694.1:c.-12G>A, NM_001354695.1:c.-12G>A, NR_148940.1:n.534G>A, NR_148941.1:n.534G>A, NR_148942.1:n.534G>A, XM_011533974.3:c.119G>A, XM_017006966.1:c.119G>A, XR_001740227.1:n.450G>A, ENST00000251849.8:c.119G>A, ENST00000416093.1:c.119G>A, ENST00000423275.5:c.119G>A, ENST00000442415.6:c.119G>A, NC_000003.12:g.12618603C>T, CM000665.2:g.12618603C>T, NC_000003.11:g.12660102C>T, CM000665.1:g.12660102C>T, NC_000003.10:g.12635102C>T, NG_007467.1:g.50577G>A, LRG_413:g.50577G>A, NM_002880.3(RAF1):c.119G>A (p.Arg40His) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BS4 [MET], BP5 [MET], BA1 [MET] The filtering allele frequency of the c.119G>A (p.Arg40His) variant in the RAF1 gene is 0.082% for Latino chromosomes by the Exome Aggregation Consortium (112/11578 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additionally, the variant did not segregate with disease in affected family members (BS4; GeneDx internal data; GTR ID: 26957; ClinVar SCV000171283.11; SCV000227278.4). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data; GTR ID: 26957; SCV000171283.11). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BS4, BP5. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA201617/MONDO:0021060/004 0.0003 Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 3 12633207 40614 C A NM_002880.3(RAF1):c.1193G>T (p.Arg398Leu) 40614 CA235336 NM_002880.3:c.1193G>T, NC_000003.12:g.12591708C>A, CM000665.2:g.12591708C>A, NC_000003.11:g.12633207C>A, CM000665.1:g.12633207C>A, NC_000003.10:g.12608207C>A, NG_007467.1:g.77472G>T, LRG_413:g.77472G>T, LRG_413t1:c.1193G>T, XM_005265355.1:c.1193G>T, XM_005265357.1:c.1094G>T, XM_005265358.3:c.950G>T, XM_005265359.3:c.851G>T, XM_005265360.1:c.1193G>T, XM_011533974.1:c.1193G>T, XM_011533975.1:c.950G>T, NM_001354689.1:c.1253G>T, NM_001354690.1:c.1193G>T, NM_001354691.1:c.950G>T, NM_001354692.1:c.950G>T, NM_001354693.1:c.1094G>T, NM_001354694.1:c.1010G>T, NM_001354695.1:c.851G>T, NR_148940.1:n.1721G>T, NR_148941.1:n.1667G>T, NR_148942.1:n.1606G>T, XM_011533974.3:c.1193G>T, XM_017006966.1:c.1094G>T, XR_001740227.1:n.1484G>T, ENST00000251849.8:c.1193G>T, ENST00000423275.5:c.*870G>T, ENST00000432427.2:n.830G>T, ENST00000442415.6:c.1253G>T, ENST00000460610.1:n.150G>T, ENST00000465826.5:n.550G>T, ENST00000475353.1:n.361G>T, ENST00000494557.1:n.209G>T, NM_002880.3(RAF1):c.1193G>T (p.Arg398Leu) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Uncertain Significance PP3 [MET], PP2 [MET], PM2 [MET] The c.1193G>T (p.Arg398Leu) variant has been identified in patients with clinical features of a RASopathy (PS4 not met; GeneDx, GGC internal data; GTR ID: 26957, 1019; ClinVar SCV000209025.5; SCV000207671.1). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg398Leu variant may impact the protein (PP3). In summary, the clinical significance of the p.Arg398Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PP2, PP3. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA235336/MONDO:0021060/004 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 3 12626702 40620 C T NM_002880.3(RAF1):c.1587G>A (p.Ser529=) 40620 CA2259466 NM_002880.3:c.1587G>A, LRG_413t1:c.1587G>A, XM_005265355.1:c.1587G>A, XM_005265357.1:c.1488G>A, XM_005265358.3:c.1344G>A, XM_005265359.3:c.1245G>A, XM_011533974.1:c.1587G>A, XM_011533975.1:c.1344G>A, NM_001354689.1:c.1647G>A, NM_001354690.1:c.1587G>A, NM_001354691.1:c.1344G>A, NM_001354692.1:c.1344G>A, NM_001354693.1:c.1488G>A, NM_001354694.1:c.1404G>A, NM_001354695.1:c.1245G>A, NR_148940.1:n.2115G>A, NR_148941.1:n.2061G>A, NR_148942.1:n.2000G>A, XM_011533974.3:c.1587G>A, XM_017006966.1:c.1488G>A, ENST00000251849.8:c.1587G>A, ENST00000423275.5:c.*1264G>A, ENST00000432427.2:n.1224G>A, ENST00000442415.6:c.1647G>A, ENST00000471449.1:n.276G>A, NC_000003.12:g.12585203C>T, CM000665.2:g.12585203C>T, NC_000003.11:g.12626702C>T, CM000665.1:g.12626702C>T, NC_000003.10:g.12601702C>T, NG_007467.1:g.83977G>A, LRG_413:g.83977G>A, NM_002880.3(RAF1):c.1587G>A (p.Ser529=) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1587G>A (p.Ser529=) variant in the RAF1 gene is 0.052% (10/10402) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA2259466/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 3 12626660 40621 C G NM_002880.3(RAF1):c.1629G>C (p.Thr543=) 40621 CA235376 NM_002880.3:c.1629G>C, LRG_413t1:c.1629G>C, XM_005265355.1:c.1629G>C, XM_005265357.1:c.1530G>C, XM_005265358.3:c.1386G>C, XM_005265359.3:c.1287G>C, XM_011533974.1:c.1629G>C, XM_011533975.1:c.1386G>C, NM_001354689.1:c.1689G>C, NM_001354690.1:c.1629G>C, NM_001354691.1:c.1386G>C, NM_001354692.1:c.1386G>C, NM_001354693.1:c.1530G>C, NM_001354694.1:c.1446G>C, NM_001354695.1:c.1287G>C, NR_148940.1:n.2157G>C, NR_148941.1:n.2103G>C, NR_148942.1:n.2042G>C, XM_011533974.3:c.1629G>C, XM_017006966.1:c.1530G>C, ENST00000251849.8:c.1629G>C, ENST00000423275.5:c.*1306G>C, ENST00000432427.2:n.1266G>C, ENST00000442415.6:c.1689G>C, ENST00000471449.1:n.318G>C, NC_000003.12:g.12585161C>G, CM000665.2:g.12585161C>G, NC_000003.11:g.12626660C>G, CM000665.1:g.12626660C>G, NC_000003.10:g.12601660C>G, NG_007467.1:g.84019G>C, LRG_413:g.84019G>C, NM_002880.3(RAF1):c.1629G>C (p.Thr543=) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1629G>C (p.Thr543=) variant in the RAF1 gene is 0.054% (9/8654) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA235376/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 2 39262409 40664 G A NM_005633.3(SOS1):c.1018C>T (p.Pro340Ser) 40664 CA1624660 NM_005633.3:c.1018C>T, LRG_754t1:c.1018C>T, XM_005264515.3:c.1018C>T, XM_011533060.1:c.1111C>T, XM_011533061.1:c.1111C>T, XM_011533062.1:c.997C>T, XM_011533063.1:c.994C>T, XM_011533064.1:c.847C>T, XM_011533065.1:c.1111C>T, XM_005264515.4:c.1018C>T, XM_011533062.2:c.997C>T, XM_011533064.2:c.847C>T, ENST00000395038.6:c.1018C>T, ENST00000402219.6:c.1018C>T, ENST00000426016.5:c.1018C>T, ENST00000461545.1:n.368C>T, NC_000002.12:g.39035268G>A, CM000664.2:g.39035268G>A, NC_000002.11:g.39262409G>A, CM000664.1:g.39262409G>A, NC_000002.10:g.39115913G>A, NG_007530.1:g.90196C>T, LRG_754:g.90196C>T, NM_005633.3(SOS1):c.1018C>T (p.Pro340Ser) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign PP2 [MET], PP3 [Unmet], PP1 [Unmet], BS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS2 [Unmet], PS4 [Unmet], PS3 [Unmet], BP5 [MET], BP7 [Unmet], BS1 [MET], BS4 [MET], BS3 [Unmet], PM2 [Unmet], PM6 [Unmet], BP1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], BA1 [Unmet] The c.1018C>T (p.Pro340Ser) variant in the SOS1 gene has been found not to segregate in a family member of a patient who underwent testing for RASopathies as well as another adult who was unaffected (BS4; GeneDx, Invitae internal data; GTR Lab ID: 26957, 500031; SCV000514724.5, SCV000659124.2). This variant has also been identified in a patient with an alternate molecular basis of disease (BP5; PMID 22585553). The filtering allele frequency of the p.Pro340Ser variant is 0.022% for East Asian exomes in the gnomAD database (20/251276 with 95% CI), which is high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5, BS1. 22585553 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA1624660/MONDO:0021060/004 0.6752 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 2 39249799 40687 C T NM_005633.3(SOS1):c.1770G>A (p.Glu590=) 40687 CA1624555 NM_005633.3:c.1770G>A, LRG_754t1:c.1770G>A, XM_005264515.3:c.1770G>A, XM_011533060.1:c.1863G>A, XM_011533061.1:c.1863G>A, XM_011533062.1:c.1749G>A, XM_011533063.1:c.1746G>A, XM_011533064.1:c.1599G>A, XM_011533065.1:c.1863G>A, XM_011533066.1:c.705G>A, XM_005264515.4:c.1770G>A, XM_011533062.2:c.1749G>A, XM_011533064.2:c.1599G>A, ENST00000395038.6:c.1770G>A, ENST00000402219.6:c.1770G>A, ENST00000426016.5:c.1770G>A, NC_000002.12:g.39022658C>T, CM000664.2:g.39022658C>T, NC_000002.11:g.39249799C>T, CM000664.1:g.39249799C>T, NC_000002.10:g.39103303C>T, NG_007530.1:g.102806G>A, LRG_754:g.102806G>A, NM_005633.3(SOS1):c.1770G>A (p.Glu590=) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1770G>A (p.Glu590=) variant in the SOS1 gene is 0.29% (34/8634) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624555/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 2 39240612 40698 C G NM_005633.3(SOS1):c.2156G>C (p.Gly719Ala) 40698 CA297202 NM_005633.3:c.2156G>C, NC_000002.12:g.39013471C>G, CM000664.2:g.39013471C>G, NC_000002.11:g.39240612C>G, CM000664.1:g.39240612C>G, NC_000002.10:g.39094116C>G, NG_007530.1:g.111993G>C, LRG_754:g.111993G>C, LRG_754t1:c.2156G>C, XM_005264515.3:c.2156G>C, XM_011533060.1:c.2249G>C, XM_011533061.1:c.2249G>C, XM_011533062.1:c.2135G>C, XM_011533063.1:c.2132G>C, XM_011533064.1:c.1985G>C, XM_011533065.1:c.2249G>C, XM_011533066.1:c.1091G>C, XM_005264515.4:c.2156G>C, XM_011533062.2:c.2135G>C, XM_011533064.2:c.1985G>C, ENST00000395038.6:c.2156G>C, ENST00000402219.6:c.2156G>C, ENST00000426016.5:c.2156G>C, NM_005633.3(SOS1):c.2156G>C (p.Gly719Ala) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.2156G>C (p.Gly719Ala) variant in the SOS1 gene is 0.0414% (37/66598) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA297202/MONDO:0021060/004 0.0059 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 2 39213367 40733 G C NM_005633.3(SOS1):c.3600C>G (p.Asp1200Glu) 40733 CA297240 NM_005633.3:c.3600C>G, LRG_754t1:c.3600C>G, XM_005264515.3:c.3555C>G, XM_011533060.1:c.3693C>G, XM_011533061.1:c.3648C>G, XM_011533062.1:c.3579C>G, XM_011533063.1:c.3576C>G, XM_011533064.1:c.3429C>G, XM_011533065.1:c.3604-863C>G, XM_011533066.1:c.2535C>G, XM_005264515.4:c.3555C>G, XM_011533062.2:c.3579C>G, XM_011533064.2:c.3429C>G, ENST00000395038.6:c.3555C>G, ENST00000402219.6:c.3600C>G, ENST00000426016.5:c.3600C>G, ENST00000469581.1:n.343C>G, NC_000002.12:g.38986226G>C, CM000664.2:g.38986226G>C, NC_000002.11:g.39213367G>C, CM000664.1:g.39213367G>C, NC_000002.10:g.39066871G>C, NG_007530.1:g.139238C>G, LRG_754:g.139238C>G, NM_005633.3(SOS1):c.3600C>G (p.Asp1200Glu) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], BS2 [Unmet], PM1 [Unmet], PM4 [Unmet], PM5 [Unmet], PS4 [Unmet], PS3 [Unmet], PS2 [Unmet], PS1 [Unmet], BP5 [MET], BP7 [Unmet], BS1 [MET], BS4 [Unmet], BS3 [Unmet], PM2 [Unmet], PM6 [Unmet], BP1 [Unmet], BP4 [MET], BP2 [Unmet], BP3 [Unmet], BA1 [Unmet] The c.3600C>G (p.Asp1200Glu) variant in the SOS1 gene has been identified in at least 6 individuals without detailed phenotypic information as well as one patient with an alternative molecular basis for disease in the BRAF gene (BP5; EGL, Invitae, GeneDx internal data, GTR Lab ID: 500060, 500031, 26957; SCV000854873.1, SCV000553268.3, SCV000209087.11). The filtering allele frequency of the c.3600C>G (p.Asp1200Glu) variant is 0.025% for European (non-Finnish) exomes by the gnomAD database (40/251300 with 95% CI) which is strong evidence to suggest that the variant may be benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BS1). Of note, the c.3600C>A change that also results in p.Asp1200Glu has been identified in one patient with a RASopathy but this variant has not met criteria to be classified as pathogenic and therefore PM5 is not met (Partners LMM internal data; GTR Lab ID: 21766; SCV000062231.5). Computational prediction tools and conservation analysis suggest that the p.Asp1200Glu variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP4, BP5. 27236105 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA297240/MONDO:0021060/004 0.1 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 0, 0] 1 Uncertain Significance 19 4117429 40787 G T NM_030662.3(MAP2K2):c.291C>A (p.Ile97=) 40787 CA9091060 NM_030662.3:c.291C>A, NC_000019.10:g.4117431G>T, CM000681.2:g.4117431G>T, NC_000019.9:g.4117429G>T, CM000681.1:g.4117429G>T, NC_000019.8:g.4068429G>T, NG_007996.1:g.11698C>A, LRG_750:g.11698C>A, LRG_750t1:c.291C>A, XM_006722799.2:c.291C>A, XM_017026989.1:c.291C>A, XM_017026990.1:c.291C>A, XM_017026991.1:c.291C>A, ENST00000262948.9:c.291C>A, ENST00000394867.8:c.-1C>A, ENST00000599345.1:n.488C>A, NM_030662.3(MAP2K2):c.291C>A (p.Ile97=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.291C>A (p.Ile97=) variant in the MAP2K2 gene is 0.182% (23/8614) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA9091060/MONDO:0021060/004 0.0003 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 19 4101030 40818 C A NM_030662.3(MAP2K2):c.692G>T (p.Arg231Leu) 40818 CA296133 NM_030662.3:c.692G>T, NC_000019.10:g.4101032C>A, CM000681.2:g.4101032C>A, NC_000019.9:g.4101030C>A, CM000681.1:g.4101030C>A, NC_000019.8:g.4052030C>A, NG_007996.1:g.28097G>T, LRG_750:g.28097G>T, LRG_750t1:c.692G>T, XM_006722799.2:c.692G>T, XM_011528133.1:c.122G>T, XM_017026989.1:c.692G>T, XM_017026990.1:c.692G>T, XM_017026991.1:c.692G>T, ENST00000262948.9:c.692G>T, ENST00000394867.8:c.401G>T, ENST00000593364.5:n.639G>T, ENST00000597008.5:n.293G>T, ENST00000597263.5:n.156G>T, ENST00000599021.1:n.16G>T, ENST00000601786.5:n.993G>T, ENST00000602167.5:n.412G>T, NM_030662.3(MAP2K2):c.692G>T (p.Arg231Leu) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Uncertain Significance BS2 [Unmet], PP2 [MET], PP3 [MET], PP1 [Unmet], PS4-Supporting [MET], PM1 [Unmet], PM4 [Unmet], PM5 [Unmet], PS3 [Unmet], PS1 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP5 [Unmet], BP7 [Unmet], PM2 [MET], PM6 [Unmet], BA1 [Unmet], BP1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet] The c.692G>T (p.Arg231Leu) variant has been identified in at least 2 independent occurrences in patients with clinical features of RASopathies (PS4_Supporting GeneDx, Invitae internal data, GTR Lab IDs 26957, 500031; ClinVar SCV000207960.9, SCV000551455.2). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg231Leu variant may impact the protein (PP3).In summary, the clinical significance of the p.Arg231Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PP2, PP3. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA296133/MONDO:0021060/004 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 19 4099300 40824 T C NM_030662.3(MAP2K2):c.818A>G (p.Lys273Arg) 40824 CA296139 NM_030662.3:c.818A>G, LRG_750t1:c.818A>G, XM_006722799.2:c.705+1717A>G, XM_011528133.1:c.248A>G, XM_017026989.1:c.818A>G, XM_017026990.1:c.705+1717A>G, ENST00000262948.9:c.818A>G, ENST00000394867.8:c.527A>G, ENST00000593364.5:n.765A>G, ENST00000595715.1:n.633A>G, ENST00000597263.5:n.169+1717A>G, ENST00000599021.1:n.29+1717A>G, ENST00000600584.5:n.1378A>G, ENST00000601786.5:n.1119A>G, NC_000019.10:g.4099302T>C, CM000681.2:g.4099302T>C, NC_000019.9:g.4099300T>C, CM000681.1:g.4099300T>C, NC_000019.8:g.4050300T>C, NG_007996.1:g.29827A>G, LRG_750:g.29827A>G, NM_030662.3(MAP2K2):c.818A>G (p.Lys273Arg) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.818A>G (p.Lys273Arg) variant in the MAP2K2 gene is 0.0368% (6/7088) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA296139/MONDO:0021060/004 0.0003 Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 19 4099195 40834 G A NM_030662.3(MAP2K2):c.919+4C>T 40834 CA9090795 NM_030662.3:c.919+4C>T, LRG_750t1:c.919+4C>T, XM_006722799.2:c.705+1822C>T, XM_011528133.1:c.349+4C>T, XM_017026989.1:c.919+4C>T, XM_017026990.1:c.705+1822C>T, ENST00000262948.9:c.919+4C>T, ENST00000394867.8:c.628+4C>T, ENST00000593364.5:n.870C>T, ENST00000595715.1:n.734+4C>T, ENST00000597263.5:n.169+1822C>T, ENST00000599021.1:n.29+1822C>T, ENST00000600584.5:n.1479+4C>T, ENST00000601786.5:n.1220+4C>T, NC_000019.10:g.4099197G>A, CM000681.2:g.4099197G>A, NC_000019.9:g.4099195G>A, CM000681.1:g.4099195G>A, NC_000019.8:g.4050195G>A, NG_007996.1:g.29932C>T, LRG_750:g.29932C>T, NM_030662.3(MAP2K2):c.919+4C>T MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS2 [Unmet], BS1 [Unmet], BP7 [MET], BP4 [MET] The variant c.919+4C>T is an intronic variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). Also, computational prediction tools and conservation analysis suggests that the variant does not impact the protein (BP4). In summary, the clinical significance of the c.919+4C>T variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP4, BP7. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA9090795/MONDO:0021060/004 0.0507 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 14 23894115 42913 CCTT C NM_000257.3(MYH7):c.2539_2541delAAG (p.Lys847del) 42913 CA012568 NM_000257.3:c.2539_2541delAAG, NC_000014.9:g.23424909_23424911del, CM000676.2:g.23424909_23424911del, NC_000014.8:g.23894118_23894120del, CM000676.1:g.23894118_23894120del, NC_000014.7:g.22963958_22963960del, NG_007884.1:g.15753_15755del, LRG_384:g.15753_15755del, NM_000257.3:c.2539_2541del, XR_245686.3:n.2645_2647del, XM_017021340.1:c.2539_2541del, NM_000257.4:c.2539_2541del, ENST00000355349.3:c.2539_2541del, NM_000257.3(MYH7):c.2539_2541delAAG (p.Lys847del) MYH7 hypertrophic cardiomyopathy MONDO:0005045 Autosomal dominant inheritance Likely Pathogenic PS4 [MET], PM2 [MET], PM4 [MET], PP1 [MET] The c.2539_2541del (p.Lys847del) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID:15358028; PMID:22429680; PMID:23233322; PMID:24093860; PMID:18258667; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000059453.5; Invitae ClinVar SCV000219043.3). This variant segregated with disease in 3 affected individuals (PP1; Partners LMM ClinVar SCV000059453.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant is a deletion of 1 amino acid at position 847 and is not predicted to alter the protein reading-frame (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM2; PM4; PP1 18258667, 22429680, 15358028, 24093860, 23233322 Cardiovascular Cardiomyopathy VCEP https://www.nature.com/articles/gim2017218#t1 2016-12-15 2018-11-16 false https://erepo.genome.network/evrepo/ui/classification/CA012568/MONDO:0005045/002 0.9878 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 14 23893244 42934 TCTC T NM_000257.3(MYH7):c.2791_2793delGAG (p.Glu931del) 42934 CA013089 NM_000257.3:c.2791_2793delGAG, NM_000257.3:c.2791_2793del, XR_245686.3:n.2897_2899del, XM_017021340.1:c.2791_2793del, NM_000257.4:c.2791_2793del, ENST00000355349.3:c.2791_2793del, NC_000014.9:g.23424042_23424044del, CM000676.2:g.23424042_23424044del, NC_000014.8:g.23893251_23893253del, CM000676.1:g.23893251_23893253del, NC_000014.7:g.22963091_22963093del, NG_007884.1:g.16624_16626del, LRG_384:g.16624_16626del, NM_000257.3(MYH7):c.2791_2793delGAG (p.Glu931del) MYH7 hypertrophic cardiomyopathy MONDO:0005045 Autosomal dominant inheritance Likely Pathogenic PS4-Supporting [MET], PP1-Moderate [MET], PM2 [MET], PM4 [MET] The c.2791_2793del (p.Glu931del) variant in MYH7 has been reported in 4 individuals with hypertrophic cardiomyopathy (PS4_Supporting; PMID:9829907; PMID:12707239; PMID:27532257; Partners LMM ClinVar SCV000059478.5). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:9829907). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant is a deletion of 1 amino acid at position 931 and is not predicted to alter the protein reading-frame (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM2; PM4; PP1_Moderate; PS4_ Supporting 9829907, 12707239, 27532257, 9829907 Cardiovascular Cardiomyopathy VCEP https://www.nature.com/articles/gim2017218#t1 2016-12-15 2018-11-16 false https://erepo.genome.network/evrepo/ui/classification/CA013089/MONDO:0005045/002 0.9878 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 14 23889445 42956 T TG NM_000257.3(MYH7):c.3337-3dupC 42956 CA013590 NM_000257.3:c.3337-3dupC, NM_000257.3:c.3337-3_3337-2insC, NC_000014.9:g.23420238dup, CM000676.2:g.23420238dup, NC_000014.8:g.23889447dup, CM000676.1:g.23889447dup, NC_000014.7:g.22959287dup, NG_007884.1:g.20425dup, LRG_384:g.20425dup, NM_000257.3:c.3337-3dup, XR_245686.3:n.3445-3dup, XM_017021340.1:c.3337-3dup, NM_000257.4:c.3337-3dup, ENST00000355349.3:c.3337-3dup, NM_000257.3(MYH7):c.3337-3dupC MYH7 cardiomyopathy MONDO:0004994 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.3337-3dupC variant in the MYH7 gene is 0.23% (146/54400) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiovascular Cardiomyopathy VCEP https://www.nature.com/articles/gim2017218#t1 2016-12-15 2018-11-16 false https://erepo.genome.network/evrepo/ui/classification/CA013590/MONDO:0004994/002 0 Benign auto Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=1 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 14 23889119 42968 TCTC T NM_000257.3(MYH7):c.3658_3660delGAG (p.Glu1220del) 42968 CA013921 NM_000257.3:c.3658_3660delGAG, NC_000014.9:g.23419913_23419915del, CM000676.2:g.23419913_23419915del, NC_000014.8:g.23889122_23889124del, CM000676.1:g.23889122_23889124del, NC_000014.7:g.22958962_22958964del, NG_007884.1:g.20749_20751del, LRG_384:g.20749_20751del, NM_000257.3:c.3658_3660del, XM_017021340.1:c.3658_3660del, NM_000257.4:c.3658_3660del, ENST00000355349.3:c.3658_3660del, NM_000257.3(MYH7):c.3658_3660delGAG (p.Glu1220del) MYH7 Ebstein anomaly MONDO:0009144 Autosomal dominant inheritance Likely Pathogenic PS4-Supporting [MET], PM2 [MET], PM4 [MET], PP1 [MET] The c.3658_3660del (p.Glu1220del) variant in MYH7 has been reported in 2 individuals with Ebstein anomaly (PS4_Supporting; PMID:21127202; Partners LMM ClinVar SCV000059512.5). This variant segregated with disease in 3 affected individuals (PP1; Partners LMM ClinVar SCV000059512.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant is a deletion of 1 amino acid at position 1220 and is not predicted to alter the protein reading-frame (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for Ebstein anomaly in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM2; PM4; PP1; PS4_ Supporting 21127202 Cardiovascular Cardiomyopathy VCEP https://www.nature.com/articles/gim2017218#t1 2016-12-15 2018-11-16 false https://erepo.genome.network/evrepo/ui/classification/CA013921/MONDO:0009144/002 0.9878 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 11 76870496 43134 G A NM_000260.3(MYO7A):c.1007G>A (p.Arg336His) 43134 CA132194 NM_000260.3:c.1007G>A, NC_000011.10:g.77159450G>A, CM000673.2:g.77159450G>A, NC_000011.9:g.76870496G>A, CM000673.1:g.76870496G>A, NC_000011.8:g.76548144G>A, NG_009086.1:g.36187G>A, NM_001127179.2:c.1007G>A, NM_001127180.1:c.1007G>A, XM_005274012.2:c.1007G>A, XM_006718558.2:c.1007G>A, XM_006718559.2:c.1007G>A, XM_006718560.2:c.1007G>A, XM_006718561.2:c.1007G>A, XM_011545044.1:c.1007G>A, XM_011545045.1:c.1007G>A, XM_011545046.1:c.974G>A, XM_011545047.1:c.1007G>A, XM_011545048.1:c.1007G>A, XM_011545049.1:c.850-713G>A, XM_011545050.1:c.749G>A, XM_011545051.1:c.1007G>A, XM_011545052.1:c.1007G>A, XR_949938.1:n.1327G>A, XR_949941.1:n.1327G>A, XR_949942.1:n.1329G>A, XR_949943.1:n.1329G>A, XM_011545044.2:c.1007G>A, XM_011545046.2:c.1097G>A, XM_011545050.2:c.749G>A, XM_017017778.1:c.1097G>A, XM_017017779.1:c.1097G>A, XM_017017780.1:c.1097G>A, XM_017017781.1:c.1097G>A, XM_017017782.1:c.1097G>A, XM_017017783.1:c.1097G>A, XM_017017784.1:c.1097G>A, XM_017017785.1:c.940-713G>A, XM_017017786.1:c.1097G>A, XM_017017787.1:c.1097G>A, XM_017017788.1:c.1097G>A, XR_001747885.1:n.1112G>A, XR_001747886.1:n.1112G>A, XR_001747887.1:n.1112G>A, XR_001747888.1:n.1112G>A, XR_001747889.1:n.1112G>A, NM_000260.4:c.1007G>A, ENST00000409619.6:c.974G>A, ENST00000409709.7:c.1007G>A, ENST00000409893.5:c.1007G>A, ENST00000458637.6:c.1007G>A, ENST00000620575.4:c.1007G>A, NM_000260.3(MYO7A):c.1007G>A (p.Arg336His) MYO7A nonsyndromic genetic deafness MONDO:0019497 Uncertain Significance PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [MET], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet], BS1-Supporting [MET], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], PM5 [Unmet], BP7 [Unmet], BP5 [Unmet], BS4 [Unmet] The filtering allele frequency of the p.Arg336His variant in the MYO7A gene is 0.20% (275/126030) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a higher frequency than would be expected for an autosomal recessive pathogenic hearing loss variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Computational prediction tools and conservation analysis suggest that the p.Arg336His variant may impact the protein (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMG criteria applied: PP3, BS1_Supporting. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-17 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA132194/MONDO:0019497/005 0.6752 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 11 76866991 43201 C T NM_000260.3(MYO7A):c.324C>T (p.Tyr108=) 43201 CA132282 NM_000260.3:c.324C>T, NC_000011.10:g.77155945C>T, CM000673.2:g.77155945C>T, NC_000011.9:g.76866991C>T, CM000673.1:g.76866991C>T, NC_000011.8:g.76544639C>T, NG_009086.1:g.32682C>T, NM_001127179.2:c.324C>T, NM_001127180.1:c.324C>T, XM_005274012.2:c.324C>T, XM_006718558.2:c.324C>T, XM_006718559.2:c.324C>T, XM_006718560.2:c.324C>T, XM_006718561.2:c.324C>T, XM_011545044.1:c.324C>T, XM_011545045.1:c.324C>T, XM_011545046.1:c.291C>T, XM_011545047.1:c.324C>T, XM_011545048.1:c.324C>T, XM_011545049.1:c.324C>T, XM_011545050.1:c.66C>T, XM_011545051.1:c.324C>T, XM_011545052.1:c.324C>T, XR_949938.1:n.644C>T, XR_949941.1:n.644C>T, XR_949942.1:n.646C>T, XR_949943.1:n.646C>T, XM_011545044.2:c.324C>T, XM_011545046.2:c.414C>T, XM_011545050.2:c.66C>T, XM_017017778.1:c.414C>T, XM_017017779.1:c.414C>T, XM_017017780.1:c.414C>T, XM_017017781.1:c.414C>T, XM_017017782.1:c.414C>T, XM_017017783.1:c.414C>T, XM_017017784.1:c.414C>T, XM_017017785.1:c.414C>T, XM_017017786.1:c.414C>T, XM_017017787.1:c.414C>T, XM_017017788.1:c.414C>T, XR_001747885.1:n.429C>T, XR_001747886.1:n.429C>T, XR_001747887.1:n.429C>T, XR_001747888.1:n.429C>T, XR_001747889.1:n.429C>T, NM_000260.4:c.324C>T, ENST00000409619.6:c.291C>T, ENST00000409709.7:c.324C>T, ENST00000409893.5:c.324C>T, ENST00000458637.6:c.324C>T, ENST00000620575.4:c.324C>T, NM_000260.3(MYO7A):c.324C>T (p.Tyr108=) MYO7A nonsyndromic genetic deafness MONDO:0019497 Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [MET], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The filtering allele frequency of the p.Tyr108= variant in the MYO7A gene is 1.45% (300/18658) of East Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA132282/MONDO:0019497/005 0.0014 Benign Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 7 107329565 43491 G A NM_000441.1(SLC26A4):c.1069G>A (p.Ala357Thr) 43491 CA132654 NM_000441.1:c.1069G>A, XM_005250425.1:c.1069G>A, XM_006716025.2:c.1069G>A, XM_005250425.2:c.1069G>A, XM_006716025.3:c.1069G>A, XM_017012318.1:c.1069G>A, ENST00000265715.7:c.1069G>A, NC_000007.14:g.107689120G>A, CM000669.2:g.107689120G>A, NC_000007.13:g.107329565G>A, CM000669.1:g.107329565G>A, NC_000007.12:g.107116801G>A, NG_008489.1:g.33486G>A, NM_000441.1(SLC26A4):c.1069G>A (p.Ala357Thr) SLC26A4 Pendred syndrome MONDO:0010134 Autosomal recessive inheritance Benign PP3 [MET], BP4 [Unmet], BA1 [MET], PS1 [Unmet], PS4 [Unmet], PM5 [Unmet], PM1 [Unmet], BP5 [Unmet] The filtering allele frequency of the p.Ala357Thr variant in the SLC26A4 gene is 0.47% for African chromosomes by gnomAD (136/24968 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Pendred syndrome variants (BA1). The REVEL computational prediction analysis tool produces a score of 0.849, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA132654/MONDO:0010134/005 0.3246 Likely Pathogenic Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[1, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 15 66782108 44586 CTATT C NM_002755.3(MAP2K1):c.1068+12_1068+15delTATT 44586 CA134591 NM_002755.3:c.1068+8_1068+11delTATT, NM_002755.3:c.1068+12_1068+15delTATT, NC_000015.10:g.66489775_66489778del, CM000677.2:g.66489775_66489778del, NC_000015.9:g.66782113_66782116del, CM000677.1:g.66782113_66782116del, NC_000015.8:g.64569167_64569170del, NG_008305.1:g.107903_107906del, LRG_725:g.107903_107906del, NG_051234.1:g.13042_13045del, NM_002755.3:c.1068+12_1068+15del, LRG_725t1:c.1068+12_1068+15del, XM_011521783.1:c.1002+12_1002+15del, NM_006049.3:c.*965_*968del, NR_138061.1:n.1484_1487del, XM_011521783.3:c.1002+12_1002+15del, XM_017022411.2:c.990+12_990+15del, XM_017022412.1:c.924+12_924+15del, XM_017022413.1:c.540+12_540+15del, ENST00000307102.9:c.1068+12_1068+15del, ENST00000566326.1:c.540+12_540+15del, NM_002755.3(MAP2K1):c.1068+12_1068+15delTATT MAP2K1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1068+12_1068+15delTATT variant in the MAP2K1 gene is 0.285% (214/66740) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA134591/MONDO:0021060/004 0.0014 Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 13 20763687 44740 C A NM_004004.5(GJB2):c.34G>T (p.Gly12Cys) 44740 CA172224 NM_004004.5:c.34G>T, NC_000013.11:g.20189548C>A, CM000675.2:g.20189548C>A, NC_000013.10:g.20763687C>A, CM000675.1:g.20763687C>A, NC_000013.9:g.19661687C>A, NG_008358.1:g.8428G>T, XM_011535049.1:c.34G>T, XM_011535049.2:c.34G>T, NM_004004.6:c.34G>T, ENST00000382844.1:c.34G>T, ENST00000382848.4:c.34G>T, NM_004004.5(GJB2):c.34G>T (p.Gly12Cys) GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Likely Pathogenic PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [MET], PP4 [Unmet], PP1 [Unmet], PM3-Very Strong [MET], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS2 [Unmet], PS4 [Unmet], PS3 [Unmet], PM5 [MET], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [MET], BS4 [Unmet] The filtering allele frequency of the p.Gly12Cys variant in the GJB2 gene is 0.32% (129/34098) of Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/). This is a high enough frequency that, in absence of conflicting data, might warrant a likely benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). However, based on the evidence outline below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BS1 code will not contribute to the overall classification. This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; Partners LMM internal data SCV000061501.5). The p.Gly12Cys variant has also been reported in the literature in 10 individuals with hearing loss; however, a variant affecting the remaining DFNB1 allele was not reported (PMID: 15365987, 17041943, 17666888, 25288386, 26969326). A different pathogenic missense variant (p.Gly12Val) has been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 21387). Computational prediction tools and conservation analysis suggest that the p.Gly12Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VS, PM5, PP3, BS1. 25288386, 26969326, 15365987, 17041943, 17666888 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-11 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA172224/MONDO:0019497/005 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763150 44760 A G NM_004004.5(GJB2):c.571T>C (p.Phe191Leu) 44760 CA134989 NM_004004.5:c.571T>C, XM_011535049.1:c.571T>C, XM_011535049.2:c.571T>C, NM_004004.6:c.571T>C, ENST00000382844.1:c.571T>C, ENST00000382848.4:c.571T>C, NC_000013.11:g.20189011A>G, CM000675.2:g.20189011A>G, NC_000013.10:g.20763150A>G, CM000675.1:g.20763150A>G, NC_000013.9:g.19661150A>G, NG_008358.1:g.8965T>C, NM_004004.5(GJB2):c.571T>C (p.Phe191Leu) GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Uncertain Significance PS3-Supporting [MET], PP3 [MET], BS2 [MET], BS1-Supporting [MET], PS4 [Unmet], PM3-Supporting [MET] The c.571T>C (p.Phe191Leu) variant in GJB2 has been reported in over 19 Asian probands in the literature. However, a case control comparison using Chi-squared analysis did not show a statistical significance between cases and controls in the published studies, or between cases and East Asians in gnomAD (case chromosomes= 19/16415, control chromosomes = 6/8626, 36/18870 East Asian chromosomes in gnomAD; PMIDs 19366456, 15700112, 23826813, 27247933, 27792752, 12792423, 12560944, 19043807, 27627659, 20497192 and https://doi.org/10.1016/S1672-2930(07)50004-8). The filtering allele frequency of the p.Phe191Leu variant in the GJB2 gene is 0.14% for East Asian chromosomes in gnomAD (36/18870 with 95% CI), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been detected in 1 individual with hearing loss who was homozygous for the variant, and in 4 compound heterozygous individuals who had a second pathogenic GJB2 variant identified (3 with p.Val37Ile and 1 with c.235delC) (Oguchi 2005 PMID: 15700112; ARUP SCV000603821; Partners Lab for Molecular Medicine SCV000061527). Phase was not confirmed for any of these individuals. It is possible that these homozygous and compound heterozygous observations are due to the relatively high allele frequencies of these variants in gnomAD and therefore PM3 was downgraded (PM3_Supporting). In addition, this variant was reported in the homozygous state in a normal hearing parent (BS2, Wattanasirichiagoon 2004, PMID 15479191). Computational prediction analysis using REVEL suggests that the variant may impact the protein (PP3). Two in vitro functional studies demonstrates that this variant resulted in abnormal protein trafficking and retention of the protein in the endoplasmic reticulum; however, further electrical coupling studies were not performed (PS3_Supporting; PMID: 23967136, 26749107). In summary, due to conflicting evidence, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BS2, PM3_Supporting, PS3_Supporting, PP3. 25388846, 26749107, 23967136, 15479191, 16840571, 19043807, 26178431, 16840571, 12792423, 20497192, 19043807, 12560944, 23826813, 24256046, 27247933, 27792752, 15790391, 27627659, 15700112, 19366456, 15700112 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA134989/MONDO:0019497/005 0.8999 Likely Pathogenic Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 3 Uncertain Significance 12 25362762 45129 TTTC T NM_004985.4(KRAS):c.531_533delGAA (p.Lys180del) 45129 CA135584 NM_004985.4:c.531_533delGAA, NM_004985.4:c.531_533del, NM_033360.3:c.*85_*87del, XM_006719069.2:c.*85_*87del, XM_011520653.1:c.531_533del, XM_006719069.4:c.*85_*87del, XM_011520653.3:c.531_533del, ENST00000256078.8:c.*85_*87del, ENST00000311936.7:c.531_533del, ENST00000557334.5:c.192_194del, NC_000012.12:g.25209834_25209836del, CM000674.2:g.25209834_25209836del, NC_000012.11:g.25362768_25362770del, CM000674.1:g.25362768_25362770del, NC_000012.10:g.25254035_25254037del, NG_007524.1:g.46090_46092del, NM_004985.4(KRAS):c.531_533delGAA (p.Lys180del) KRAS RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BP5 [MET], BA1 [MET] The filtering allele frequency of the c.531_533delGAA (p.Lys180del) variant in the KRAS gene is 0.51% for European (non-Finnish) chromosomes by the Exome Aggregation Consortium (55/64754 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR ID's: 21766, 26957; ClinVar SCV000061947, SCV000207865). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA135584/MONDO:0021060/004 0.1 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 6 76558195 45131 C T NM_004999.3(MYO6):c.1025C>T (p.Ala342Val) 45131 CA135587 NM_004999.3:c.1025C>T, NM_001300899.1:c.1025C>T, XM_005248719.2:c.1025C>T, XM_005248720.2:c.1025C>T, XM_005248721.2:c.1025C>T, XM_005248722.2:c.1025C>T, XM_005248724.2:c.1025C>T, XM_005248726.2:c.1025C>T, XM_005248719.4:c.1025C>T, XM_005248720.4:c.1025C>T, XM_005248721.4:c.1025C>T, XM_005248722.4:c.1025C>T, XM_005248724.4:c.1025C>T, XM_005248726.4:c.1025C>T, XM_017010899.2:c.1025C>T, XM_024446447.1:c.1025C>T, XM_024446448.1:c.1025C>T, NM_004999.4:c.1025C>T, ENST00000369975.5:c.1025C>T, ENST00000369977.7:c.1025C>T, ENST00000369981.7:c.1025C>T, ENST00000369985.8:c.1025C>T, ENST00000615563.4:c.1025C>T, ENST00000627432.2:c.1025C>T, NC_000006.12:g.75848478C>T, CM000668.2:g.75848478C>T, NC_000006.11:g.76558195C>T, CM000668.1:g.76558195C>T, NC_000006.10:g.76614915C>T, NG_009934.1:g.104287C>T, NG_009934.2:g.104286C>T, NM_004999.3(MYO6):c.1025C>T (p.Ala342Val) MYO6 nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Benign PM2 [Unmet], PVS1 [Unmet], PP3 [MET], PP4 [Unmet], BP4 [Unmet], BP3 [Unmet], BA1 [MET], PS1 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], BP7 [Unmet] The filtering allele frequency of the p.Ala342Val variant in the MYO6 gene is 0.21% for European (non-Finnish) chromosomes by gnomAD (304/129090 with 95% CI), and one homozygous European (Finnish) individual, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). The REVEL computational prediction analysis tool produced a score of 0.905, however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, the HL EP classified this variant as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. 27068579 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA135587/MONDO:0019497/005 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 6 76542642 45163 G A NM_004999.3(MYO6):c.475G>A (p.Glu159Lys) 45163 CA135641 NM_004999.3:c.475G>A, NM_001300899.1:c.475G>A, XM_005248719.2:c.475G>A, XM_005248720.2:c.475G>A, XM_005248721.2:c.475G>A, XM_005248722.2:c.475G>A, XM_005248724.2:c.475G>A, XM_005248726.2:c.475G>A, XM_005248719.4:c.475G>A, XM_005248720.4:c.475G>A, XM_005248721.4:c.475G>A, XM_005248722.4:c.475G>A, XM_005248724.4:c.475G>A, XM_005248726.4:c.475G>A, XM_017010899.2:c.475G>A, XM_024446447.1:c.475G>A, XM_024446448.1:c.475G>A, NM_004999.4:c.475G>A, ENST00000369975.5:c.475G>A, ENST00000369977.7:c.475G>A, ENST00000369981.7:c.475G>A, ENST00000369985.8:c.475G>A, ENST00000615563.4:c.475G>A, ENST00000627432.2:c.475G>A, NC_000006.12:g.75832925G>A, CM000668.2:g.75832925G>A, NC_000006.11:g.76542642G>A, CM000668.1:g.76542642G>A, NC_000006.10:g.76599362G>A, NG_009934.1:g.88734G>A, NG_009934.2:g.88733G>A, NM_004999.3(MYO6):c.475G>A (p.Glu159Lys) MYO6 nonsyndromic genetic deafness MONDO:0019497 Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BA1 [MET], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The filtering allele frequency of the p.Glu159Lys variant in the MYO6 gene is 0.7% for Ashkenazi Jewish chromosomes in the Genome Aggregation Database (91/10146 with 95%CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-20 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA135641/MONDO:0019497/005 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 11 532696 45305 C T NM_005343.3(HRAS):c.510G>A (p.Lys170=) 45305 CA135992 NM_005343.3:c.510G>A, NM_001130442.1:c.510G>A, NM_005343.2:c.510G>A, NM_176795.3:c.*79G>A, XM_011519875.1:c.-425+4359C>T, XM_011519877.1:c.-162+4359C>T, XR_242795.1:n.791G>A, NM_001130442.2:c.510G>A, NM_001318054.1:c.273G>A, NM_176795.4:c.*79G>A, XM_011519875.2:c.-425+4359C>T, XM_011519877.2:c.-162+4359C>T, XM_017017167.1:c.-500+4359C>T, XM_017017168.1:c.-500+4359C>T, NM_005343.4:c.510G>A, ENST00000311189.7:c.510G>A, ENST00000397594.5:c.*79G>A, ENST00000397596.6:c.510G>A, ENST00000417302.5:c.*79G>A, ENST00000451590.5:c.510G>A, ENST00000462734.1:n.285G>A, ENST00000478324.5:n.243-66G>A, ENST00000479482.1:n.431G>A, ENST00000493230.5:c.*79G>A, NC_000011.10:g.532696C>T, CM000673.2:g.532696C>T, NC_000011.9:g.532696C>T, CM000673.1:g.532696C>T, NC_000011.8:g.522696C>T, NG_007666.1:g.7855G>A, NM_005343.3(HRAS):c.510G>A (p.Lys170=) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BP5 [MET], BP7 [MET], BP4 [MET] The c.510G>A (p.Lys170=) variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). Computational prediction tools and conservation analysis suggest that the p.Lys170= variant does not impact the protein (BP4).This variant has been identified in a patient with an alternate molecular basis for disease (BP5; LMM and GeneDx internal data; GTR ID's: 21766, 26957; ClinVar SCV000062144; SCV000168832). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP7, BP5, BP4. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA135992/MONDO:0021060/004 0.0122 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 11 120989335 45314 A G NM_005422.2(TECTA):c.1111A>G (p.Arg371Gly) 45314 CA136018 NM_005422.2:c.1111A>G, NM_005422.2:n.1111A>G, ENST00000264037.2:n.1111A>G, ENST00000392793.5:c.1111A>G, NC_000011.10:g.121118626A>G, CM000673.2:g.121118626A>G, NC_000011.9:g.120989335A>G, CM000673.1:g.120989335A>G, NC_000011.8:g.120494545A>G, NG_011633.1:g.20961A>G, NM_005422.2(TECTA):c.1111A>G (p.Arg371Gly) TECTA nonsyndromic genetic deafness MONDO:0019497 Benign PP3 [Unmet], BP4 [Unmet], BA1 [MET] The filtering allele frequency of the p.Arg317Gly variant in the TECTA gene is 67.5% (16434/24006) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant and autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA136018/MONDO:0019497/005 0 Benign auto Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=1 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 11 120998747 45317 C G NM_005422.2(TECTA):c.2061C>G (p.Asn687Lys) 45317 CA136024 NM_005422.2:c.2061C>G, NM_005422.2:n.2061C>G, ENST00000264037.2:n.2061C>G, ENST00000392793.5:c.2061C>G, NC_000011.10:g.121128038C>G, CM000673.2:g.121128038C>G, NC_000011.9:g.120998747C>G, CM000673.1:g.120998747C>G, NC_000011.8:g.120503957C>G, NG_011633.1:g.30373C>G, NM_005422.2(TECTA):c.2061C>G (p.Asn687Lys) TECTA nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Likely Benign BA1 [Unmet], BP4 [MET], PS4 [Unmet], PM3 [Unmet], BS1 [MET] The p.Asn687Lys variant in TECTA has been identified in 1 patient with Asperger syndrome who was hypersensitive to sound (PMID: 30675382). However, the filtering allele frequency of the p.Asn687Lys variant is 0.3% for European chromosomes by gnomAD (399/126054, including one homozygous observation, with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1, BP4. 30675382 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA136024/MONDO:0019497/005 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 1 216498754 48347 T G NM_206933.2(USH2A):c.1036A>C (p.Asn346His) 48347 CA262054 NM_206933.2:c.1036A>C, NC_000001.11:g.216325412T>G, CM000663.2:g.216325412T>G, NC_000001.10:g.216498754T>G, CM000663.1:g.216498754T>G, NC_000001.9:g.214565377T>G, NG_009497.1:g.102985A>C, NM_007123.5:c.1036A>C, NM_206933.3:c.1036A>C, ENST00000307340.7:c.1036A>C, ENST00000366942.3:c.1036A>C, NM_206933.2(USH2A):c.1036A>C (p.Asn346His) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Pathogenic PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP4 [MET], PP3 [MET], PM3-Very Strong [MET], PM2-Supporting [MET], BP2 [Unmet], BP4 [Unmet], BP3 [Unmet], BA1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], PS3 [Unmet], PM5 [Unmet], PM1 [Unmet], PM4 [Unmet], PP1-Strong [MET], BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet] The allele frequency of the p.Asn346His variant in the USH2A gene is 0.016% (20/126318) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The p.Asn346His variant in USH2A has been reported to segregate with hearing loss in at least 7 families including 13 family members (PP1_S; 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 15241801, 24160897, 22135276, 26969326). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). Computational prediction tools and conservation analysis suggest that the p.Asn346His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP1_S, PM3_VS, PP4, PP3. 25521520, 24160897, 10729113, 17405132, 15241801, 22135276, 24160897, 26969326, 15241801, 22135276, 24160897, 26969326, 15241801, 22135276, 25521520, 24160897, 10729113, 15241801, 17405132, 22135276, 25521520, 24160897, 10729113, 15241801, 17405132, 22135276 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA262054/MONDO:0019501/005 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 1 215807798 48459 T C NM_206933.2(USH2A):c.15297+3A>G 48459 CA143392 NM_206933.2:c.15297+3A>G, NM_206933.3:c.15297+3A>G, ENST00000307340.7:c.15297+3A>G, NC_000001.11:g.215634456T>C, CM000663.2:g.215634456T>C, NC_000001.10:g.215807798T>C, CM000663.1:g.215807798T>C, NC_000001.9:g.213874421T>C, NG_009497.1:g.793941A>G, NM_206933.2(USH2A):c.15297+3A>G USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [MET], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The filtering allele frequency of the c.15297+3A>G variant in the USH2A gene is 0.99% (265/24032) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA143392/MONDO:0019501/005 0.025 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 1 215802242 48464 C T NM_206933.2(USH2A):c.15433G>A (p.Val5145Ile) 48464 CA143401 NM_206933.2:c.15433G>A, NM_206933.3:c.15433G>A, ENST00000307340.7:c.15433G>A, NC_000001.11:g.215628900C>T, CM000663.2:g.215628900C>T, NC_000001.10:g.215802242C>T, CM000663.1:g.215802242C>T, NC_000001.9:g.213868865C>T, NG_009497.1:g.799497G>A, NM_206933.2(USH2A):c.15433G>A (p.Val5145Ile) USH2A Usher syndrome type 2 MONDO:0016484 Autosomal recessive inheritance Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BA1 [MET], BP4 [MET], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The p.Val5145Ile variant in USH2A has been identified in at least 5 individuals with Usher syndrome; however, in 3 individuals no variant on the second allele was identified and in two individuals, no information about the other allele was provided (PMIDs 28041643, 25999674, 20829743, 27353947, 23591405). Additionally, the p.Val5145Ile variant was identified in 2 alleles of 56 retinitis pigmentosa patients, however it is unclear in which one or two patients these alleles were found (PMID 20591486). The filtering allele frequency of the p.Val5145Ile variant in the USH2A gene is 0.7% for European (Finnish) chromosomes by gnomAD (201/25124 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4) .In summary, this variant meets criteria to be classified as benign based primarily on population frequency data and the absence of cases with biallelic variants. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP4. 20507924, 27353947, 25999674, 20829743, 20591486, 28041643, 23591405 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA143401/MONDO:0016484/005 0.0507 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 1 215799170 48468 T C NM_206933.2(USH2A):c.15562A>G (p.Ser5188Gly) 48468 CA143409 NM_206933.2:c.15562A>G, NM_206933.3:c.15562A>G, ENST00000307340.7:c.15562A>G, NC_000001.11:g.215625828T>C, CM000663.2:g.215625828T>C, NC_000001.10:g.215799170T>C, CM000663.1:g.215799170T>C, NC_000001.9:g.213865793T>C, NG_009497.1:g.802569A>G, NM_206933.2(USH2A):c.15562A>G (p.Ser5188Gly) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Benign BA1 [MET] The filtering allele frequency of the p.Ser5188Gly variant in the USH2A gene is 6.8% (2200/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-17 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA143409/MONDO:0019501/005 0.025 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 3 Uncertain Significance 1 216373231 48503 AAT A NM_007123.5(USH2A):c.3547_3548delAT (p.Ile1183Phefs) 48503 CA262101 NM_007123.5:c.3547_3548delAT, NM_007123.5:c.3547_3548del, NM_206933.2:c.3547_3548del, XR_922595.1:n.354+3969_354+3970del, XR_922596.1:n.354+3969_354+3970del, XR_922597.1:n.354+3969_354+3970del, XR_922598.1:n.484+3969_484+3970del, XR_922595.3:n.1076+3969_1076+3970del, XR_922596.3:n.1076+3969_1076+3970del, NM_206933.3:c.3547_3548del, ENST00000307340.7:c.3547_3548del, ENST00000366942.3:c.3547_3548del, NC_000001.11:g.216199894_216199895del, CM000663.2:g.216199894_216199895del, NC_000001.10:g.216373236_216373237del, CM000663.1:g.216373236_216373237del, NC_000001.9:g.214439859_214439860del, NG_009497.1:g.228506_228507del, NM_007123.5(USH2A):c.3547_3548delAT (p.Ile1183Phefs) USH2A Usher syndrome type 2A MONDO:0010169 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], PP4 [Unmet], PP1 [Unmet], PP3 [Unmet], BS2 [Unmet], BP2 [Unmet], BP4 [Unmet], BP3 [Unmet], BA1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], PS1 [Unmet], PM3 [Unmet], PM1 [Unmet], PM5 [Unmet], PM4 [Unmet], BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet] The p.Ile1183fs variant introduces a premature stop codon in biologically-relevant-exon 17/72 (NM_206933.2) that is predicted to lead to a truncated or absent protein in a gene wherein which loss-of-function is an established mechanism (PVS1; PMIDs: 9624053, 25211151, 20497194). The allele frequency of the p.Ile1183fs variant in USH2A is 0.0009% (1/111274) of non-Finnish European alleles in gnomAD , which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome type 2A based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PVS1, PM2). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA262101/MONDO:0010169/005 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 1 216246634 48535 C T NM_206933.2(USH2A):c.5581G>A (p.Gly1861Ser) 48535 CA262105 NM_206933.2:c.5581G>A, NR_125992.1:n.136+692C>T, NR_125993.1:n.136+692C>T, NM_206933.3:c.5581G>A, ENST00000307340.7:c.5581G>A, NC_000001.11:g.216073292C>T, CM000663.2:g.216073292C>T, NC_000001.10:g.216246634C>T, CM000663.1:g.216246634C>T, NC_000001.9:g.214313257C>T, NG_009497.1:g.355105G>A, NM_206933.2(USH2A):c.5581G>A (p.Gly1861Ser) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Pathogenic PM6 [Unmet], PVS1 [Unmet], PP3 [MET], PP1 [MET], PP4 [MET], BS2 [Unmet], PM2-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [MET], PS2 [Unmet], PM3-Strong [MET], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The allele frequency of the p.Gly1861Ser variant in USH2A is 0.017% (3/17184) of East Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). This variant has been detected in 4 patients with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3_S; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). The variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID: 26310143). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). Computational prediction tools and conservation analysis suggest that the p.Gly1861Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PM2_P, PP3, PM3_S, PP1, PP4. 26310143, 25356976, 23737954, 26310143, 26338283, 25356976, 23737954, 26310143, 26338283, 26310143 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA262105/MONDO:0019501/005 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 7 140501331 55793 A C NM_004333.4(BRAF):c.741T>G (p.Phe247Leu) 55793 CA284654 NM_004333.4:c.741T>G, LRG_299t1:c.741T>G, XM_005250045.1:c.741T>G, XM_005250046.1:c.741T>G, XM_011516529.1:c.741T>G, XM_011516530.1:c.741T>G, XR_242190.1:n.749T>G, XR_927520.1:n.749T>G, XR_927521.1:n.749T>G, XR_927522.1:n.749T>G, XR_927523.1:n.749T>G, NM_001354609.1:c.741T>G, NM_004333.5:c.741T>G, NR_148928.1:n.1046T>G, XM_017012558.1:c.741T>G, XM_017012559.1:c.741T>G, XR_001744857.1:n.749T>G, XR_001744858.1:n.749T>G, ENST00000288602.10:c.741T>G, ENST00000497784.1:n.776T>G, NC_000007.14:g.140801531A>C, CM000669.2:g.140801531A>C, NC_000007.13:g.140501331A>C, CM000669.1:g.140501331A>C, NC_000007.12:g.140147800A>C, NG_007873.3:g.128234T>G, LRG_299:g.128234T>G, NM_004333.4(BRAF):c.741T>G (p.Phe247Leu) BRAF RASopathy MONDO:0021060 Autosomal dominant inheritance Pathogenic PP2 [MET], PP3 [MET], PP1 [Unmet], BS2 [Unmet], PS4-Supporting [MET], PM1 [MET], PM4 [Unmet], PM5 [Unmet], PS2 [MET], PS3 [MET], PS1 [Unmet], BP5 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PM6 [MET], PM2 [MET], BP1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], BA1 [Unmet] The c.741T>G (p.Phe247Leu) variant in BRAF has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PM6, PS2, PS4_Supporting; GeneDx internal data; GTR Lab ID 26957; SCV000077236.10). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID: 28512244). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe247Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS2, PS3, PM1, PM2, PP2, PP3, PS4_Supporting. 28512244 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA284654/MONDO:0021060/004 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237555 92729 G T NM_000277.2(PAH):c.1068C>A (p.Tyr356Ter) 92729 CA273107 NM_000277.2:c.1068C>A, NC_000012.12:g.102843777G>T, CM000674.2:g.102843777G>T, NC_000012.11:g.103237555G>T, CM000674.1:g.103237555G>T, NC_000012.10:g.101761685G>T, NG_008690.1:g.78826C>A, NG_008690.2:g.119634C>A, NM_000277.1:c.1068C>A, XM_011538422.1:c.1011C>A, NM_001354304.1:c.1068C>A, NM_000277.3:c.1068C>A, ENST00000307000.7:c.1053C>A, ENST00000549247.6:n.827C>A, ENST00000551114.2:n.730C>A, ENST00000553106.5:c.1068C>A, ENST00000635477.1:n.172C>A, ENST00000635528.1:n.583C>A, NM_000277.2(PAH):c.1068C>A (p.Tyr356Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PVS1 [MET], PM2 [MET], PP4-Moderate [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: gnomAD MAF 0.00017; PP4_Moderate: Detected in PKU patients (PMID:25894915); PM3_Strong: in trans with p.W326X (Pathogenic), and IVS4-1G>A (Pathogenic). (PMID:25894915). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate, PM3_Strong). 25894915, 25894915 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-13 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273107/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234285 92731 G A NM_000277.1(PAH):c.1208C>T (p.Ala403Val) 92731 CA273106 NM_000277.1:c.1208C>T, NC_000012.12:g.102840507G>A, CM000674.2:g.102840507G>A, NC_000012.11:g.103234285G>A, CM000674.1:g.103234285G>A, NC_000012.10:g.101758415G>A, NG_008690.1:g.82096C>T, NG_008690.2:g.122904C>T, XM_011538422.1:c.1151C>T, NM_000277.2:c.1208C>T, NM_001354304.1:c.1208C>T, NM_000277.3:c.1208C>T, ENST00000307000.7:c.1193C>T, ENST00000551114.2:n.870C>T, ENST00000553106.5:c.1208C>T, ENST00000635477.1:n.312C>T, ENST00000635528.1:n.723C>T, NM_000277.1(PAH):c.1208C>T (p.Ala403Val) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM5 [Unmet], PM3-Very Strong [MET], PP3 [Unmet], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PP4_Moderate: Seen on 3 PKU alleles, BH4 deficiency was ruled out. Upgraded per ClinGen Metabolic WG. (PMID:8268925); PM3_VeryStrong: A403V found with 4 pathogenic variants . Upgraded per ClinGen SVI workgroup. (PMID:9429153); PS3: In vitro A403V mutant protein activity was ~43% wt. (PMID:21820508). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_VeryStrong, PS3). 8268925, 9429153, 21820508 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273106/MONDO:0009861/006 0.3246 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234215 92732 A G NM_000277.2(PAH):c.1278T>C (p.Asn426=) 92732 CA145978 NM_000277.2:c.1278T>C, NM_000277.1:c.1278T>C, XM_011538422.1:c.1221T>C, NM_001354304.1:c.1278T>C, NM_000277.3:c.1278T>C, ENST00000307000.7:c.1263T>C, ENST00000551114.2:n.940T>C, ENST00000553106.5:c.1278T>C, ENST00000635477.1:n.382T>C, ENST00000635528.1:n.793T>C, NC_000012.12:g.102840437A>G, CM000674.2:g.102840437A>G, NC_000012.11:g.103234215A>G, CM000674.1:g.103234215A>G, NC_000012.10:g.101758345A>G, NG_008690.1:g.82166T>C, NG_008690.2:g.122974T>C, NM_000277.2(PAH):c.1278T>C (p.Asn426=) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Benign BA1 [MET], BP4 [MET] PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.16641; BP4: no impact on gene in SIFT, Polyphen2, MutationTaster. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1, BP4). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA145978/MONDO:0009861/006 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 12 103306550 92736 A G NM_000277.2(PAH):c.168+19T>C 92736 CA145980 NM_000277.2:c.168+19T>C, NC_000012.12:g.102912772A>G, CM000674.2:g.102912772A>G, NC_000012.11:g.103306550A>G, CM000674.1:g.103306550A>G, NC_000012.10:g.101830680A>G, NG_008690.1:g.9831T>C, NG_008690.2:g.50639T>C, NM_000277.1:c.168+19T>C, XM_011538422.1:c.168+19T>C, NM_001354304.1:c.168+19T>C, XM_017019370.2:c.168+19T>C, NM_000277.3:c.168+19T>C, ENST00000307000.7:c.153+19T>C, ENST00000546844.1:c.168+19T>C, ENST00000548677.2:n.255+19T>C, ENST00000548928.1:n.90+19T>C, ENST00000549111.5:n.264+19T>C, ENST00000550978.6:n.152+19T>C, ENST00000551337.5:c.168+19T>C, ENST00000551988.5:n.257+19T>C, ENST00000553106.5:c.168+19T>C, ENST00000635500.1:n.136+19T>C, NM_000277.2(PAH):c.168+19T>C PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Benign PP4 [Unmet], BA1 [MET], BP4 [Unmet] PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.44942 in ExAC. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1). 23690520 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA145980/MONDO:0009861/006 0 Benign auto Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=1 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 12 103288696 92737 C T NM_000277.2(PAH):c.169G>A (p.Glu57Lys) 92737 CA220578 NM_000277.2:c.169G>A, NC_000012.12:g.102894918C>T, CM000674.2:g.102894918C>T, NC_000012.11:g.103288696C>T, CM000674.1:g.103288696C>T, NC_000012.10:g.101812826C>T, NG_008690.1:g.27685G>A, NG_008690.2:g.68493G>A, NM_000277.1:c.169G>A, XM_011538422.1:c.169G>A, NM_001354304.1:c.169G>A, XM_017019370.2:c.169G>A, NM_000277.3:c.169G>A, ENST00000307000.7:c.154G>A, ENST00000546844.1:c.169G>A, ENST00000548677.2:n.256G>A, ENST00000548928.1:n.91G>A, ENST00000549111.5:n.265G>A, ENST00000550978.6:n.153G>A, ENST00000551337.5:c.169G>A, ENST00000551988.5:n.258G>A, ENST00000553106.5:c.169G>A, ENST00000635500.1:n.137G>A, NM_000277.2(PAH):c.169G>A (p.Glu57Lys) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PP3 [Unmet], PM3-Supporting [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ESP MAF=0.00012.; PP4_Moderate: Detected in a patient with mild HPA. Assessment of the PAH, PTS, and QDPR genes was performed. (PMID:21147011); PM3-supporting: Detected with V388M, pathogenic in ClinVar, but parental testing not performed. (PMID:21147011). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_supporting). 21147011, 21147011 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220578/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103288546 92740 GGACAGTGGC G NM_000277.2(PAH):c.310_318delGCCACTGTC (p.Ala104_Val106del) 92740 CA220580 NM_000277.2:c.310_318delGCCACTGTC, NM_000277.1:c.310_318del, XM_011538422.1:c.310_318del, NM_000277.2:c.310_318del, NM_001354304.1:c.310_318del, XM_017019370.2:c.310_318del, NM_000277.3:c.310_318del, ENST00000307000.7:c.295_303del, ENST00000546844.1:c.310_318del, ENST00000548928.1:n.232_240del, ENST00000549111.5:n.406_414del, ENST00000550978.6:n.294_302del, ENST00000551337.5:c.310_318del, ENST00000551988.5:n.399_407del, ENST00000553106.5:c.310_318del, NC_000012.12:g.102894769_102894777del, CM000674.2:g.102894769_102894777del, NC_000012.11:g.103288547_103288555del, CM000674.1:g.103288547_103288555del, NC_000012.10:g.101812677_101812685del, NG_008690.1:g.27826_27834del, NG_008690.2:g.68634_68642del, NM_000277.2(PAH):c.310_318delGCCACTGTC (p.Ala104_Val106del) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM4 [MET], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Identified a single time in gnomAD (4.06e-06) and absent in ExAC; PM4: p.Ala104_Val106del; PP4: Single patient picked up on NBS with no confirmation studies, no clinical info, no Phe levels, etc. (PMID:27308838). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4, PP4). 27308838 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220580/MONDO:0009861/006 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103271326 92741 G A NM_000277.2(PAH):c.355C>T (p.Pro119Ser) 92741 CA220582 NM_000277.2:c.355C>T, NM_000277.1:c.355C>T, XM_011538422.1:c.355C>T, NM_001354304.1:c.355C>T, XM_017019370.2:c.355C>T, NM_000277.3:c.355C>T, ENST00000307000.7:c.340C>T, ENST00000549111.5:n.451C>T, ENST00000550978.6:n.339C>T, ENST00000551337.5:c.355C>T, ENST00000551988.5:n.444C>T, ENST00000553106.5:c.355C>T, NC_000012.12:g.102877548G>A, CM000674.2:g.102877548G>A, NC_000012.11:g.103271326G>A, CM000674.1:g.103271326G>A, NC_000012.10:g.101795456G>A, NG_008690.1:g.45055C>T, NG_008690.2:g.85863C>T, NM_000277.2(PAH):c.355C>T (p.Pro119Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [Unmet], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID 12655554) (PMID:21147011; PMID:12655554); PP4_Moderate: BH4 deficiency excluded (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM3_Strong, PP4_Moderate). 21147011, 21147011, 12655554 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-07-29 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220582/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103271235 92742 C A NM_000277.1(PAH):c.441+5G>T 92742 CA273112 NM_000277.1:c.441+5G>T, NC_000012.12:g.102877457C>A, CM000674.2:g.102877457C>A, NC_000012.11:g.103271235C>A, CM000674.1:g.103271235C>A, NC_000012.10:g.101795365C>A, NG_008690.1:g.45146G>T, NG_008690.2:g.85954G>T, XM_011538422.1:c.441+5G>T, NM_000277.2:c.441+5G>T, NM_001354304.1:c.441+5G>T, XM_017019370.2:c.441+5G>T, NM_000277.3:c.441+5G>T, ENST00000307000.7:c.426+5G>T, ENST00000549111.5:n.537+5G>T, ENST00000550978.6:n.430G>T, ENST00000551988.5:n.530+5G>T, ENST00000553106.5:c.441+5G>T, NM_000277.1(PAH):c.441+5G>T PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET], PS3 [MET], PM3-Strong [MET] The c.441+5G>T variant in PAH has been reported on >17 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 17935162; PMID: 23514811). This variant has an extremely low allele frequency (0.00002886) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org). This variant was detected in trans with IVS10-11g>a and p.V388M (Pathogenic in ClinVar) (PM3_Strong; PMID: 23514811). Computational prediction tools and conservation analysis suggest that the c.441+5G>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong 17935162, 23514811, 23514811 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-05-24 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273112/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260383 92743 T A NM_000277.2(PAH):c.500A>T (p.Asn167Ile) 92743 CA220584 NM_000277.2:c.500A>T, NC_000012.12:g.102866605T>A, CM000674.2:g.102866605T>A, NC_000012.11:g.103260383T>A, CM000674.1:g.103260383T>A, NC_000012.10:g.101784513T>A, NG_008690.1:g.55998A>T, NG_008690.2:g.96806A>T, NM_000277.1:c.500A>T, XM_011538422.1:c.500A>T, NM_001354304.1:c.500A>T, XM_017019370.2:c.500A>T, NM_000277.3:c.500A>T, ENST00000307000.7:c.485A>T, ENST00000549111.5:n.596A>T, ENST00000551988.5:n.530+10857A>T, ENST00000553106.5:c.500A>T, NM_000277.2(PAH):c.500A>T (p.Asn167Ile) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [Unmet], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (MAF=0.00003). Absent from gnomAD, 1000G, ESP; PP4_Moderate: Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. (PMID:26666653; PMID:9012412; PMID:10679941); PM3_Strong: Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants. (PMID:24368688; PMID:26666653). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). 10679941, 9012412, 26666653, 26666653, 24368688 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220584/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260375 92744 G C NM_000277.1(PAH):c.508C>G (p.His170Asp) 92744 CA273111 NM_000277.1:c.508C>G, XM_011538422.1:c.508C>G, NM_000277.2:c.508C>G, NM_001354304.1:c.508C>G, XM_017019370.2:c.508C>G, NM_000277.3:c.508C>G, ENST00000307000.7:c.493C>G, ENST00000549111.5:n.604C>G, ENST00000551988.5:n.530+10865C>G, ENST00000553106.5:c.508C>G, NC_000012.12:g.102866597G>C, CM000674.2:g.102866597G>C, NC_000012.11:g.103260375G>C, CM000674.1:g.103260375G>C, NC_000012.10:g.101784505G>C, NG_008690.1:g.56006C>G, NG_008690.2:g.96814C>G, NM_000277.1(PAH):c.508C>G (p.His170Asp) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP3 [MET], PP4 [MET], PM3-Strong [MET], PS3 [MET] The c.508C>G (p.His170Asp) variant in PAH has been reported in 1 patient with hyperphenylalaninemia, and 1 patient with benign persistent hyperphenylalaninemia. (PP4; PMID: 11385716). This variant has an extremely low allele frequency (0.00018) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 43% enzyme activity (PS3; PMID: 17935162). This variant was detected in trans with R261X, c.60+5G>T, c.1315+1G>A (Pathogenic in ClinVar) (PM3_Strong; PMID: 11385716; PMID: 24941924). Computational prediction tools and conservation analysis suggest that the c.829T>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM3_Strong 11385716, 24941924, 11385716, 17935162 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-07-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273111/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103249087 92746 T C NM_000277.2(PAH):c.533A>G (p.Glu178Gly) 92746 CA273110 NM_000277.2:c.533A>G, NC_000012.12:g.102855309T>C, CM000674.2:g.102855309T>C, NC_000012.11:g.103249087T>C, CM000674.1:g.103249087T>C, NC_000012.10:g.101773217T>C, NG_008690.1:g.67294A>G, NG_008690.2:g.108102A>G, NM_000277.1:c.533A>G, XM_011538422.1:c.533A>G, NM_001354304.1:c.533A>G, XM_017019370.2:c.533A>G, NM_000277.3:c.533A>G, ENST00000307000.7:c.518A>G, ENST00000549111.5:n.629A>G, ENST00000551988.5:n.554A>G, ENST00000553106.5:c.533A>G, NM_000277.2(PAH):c.533A>G (p.Glu178Gly) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. ExAC MAF=0.00017; PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.841; PS3: 39% residual phenylalanine hydroxylase activity (PMID:17935162); PP4_Moderate: Detected in 6 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen PAHEP. (PMID:18294361; PMID:9634518); PM3_Strong: In trans with 3 pathogenic variants (PMID:18294361). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong). 9634518, 18294361, 18294361, 17935162 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273110/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103248982 92747 A G NM_000277.1(PAH):c.638T>C (p.Leu213Pro) 92747 CA273109 NM_000277.1:c.638T>C, XM_011538422.1:c.638T>C, NM_000277.2:c.638T>C, NM_001354304.1:c.638T>C, XM_017019370.2:c.638T>C, NM_000277.3:c.638T>C, ENST00000307000.7:c.623T>C, ENST00000549111.5:n.734T>C, ENST00000553106.5:c.638T>C, NC_000012.12:g.102855204A>G, CM000674.2:g.102855204A>G, NC_000012.11:g.103248982A>G, CM000674.1:g.103248982A>G, NC_000012.10:g.101773112A>G, NG_008690.1:g.67399T>C, NG_008690.2:g.108207T>C, NM_000277.1(PAH):c.638T>C (p.Leu213Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM3-Very Strong [MET], PP3 [MET] The c.638T>C (p.Leu213Pro) variant in PAH has been reported in in 4 patients with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8659548; PMID: 19292873; PMID: 21147011). This variant is absent from large population studies (PM2; http://exac.broadinstitute.org). This variant was detected in trans with c.1066-11G>A, E390G, D415N, R261X.(Pathogenic in ClinVar) (PM3_Very-strong; PMID: 19292873; PMID: 21147011; PMID: 8632937). Computational prediction tools and conservation analysis suggest that the c.638T>C variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong 21147011, 8659548, 19292873, 21147011, 8632937, 19292873 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-10-01 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273109/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246700 92748 C T NM_000277.2(PAH):c.735G>A (p.Val245=) 92748 CA145982 NM_000277.2:c.735G>A, NM_000277.1:c.735G>A, XM_011538422.1:c.735G>A, NM_001354304.1:c.735G>A, NM_000277.3:c.735G>A, ENST00000307000.7:c.720G>A, ENST00000549247.6:n.494G>A, ENST00000553106.5:c.735G>A, NC_000012.12:g.102852922C>T, CM000674.2:g.102852922C>T, NC_000012.11:g.103246700C>T, CM000674.1:g.103246700C>T, NC_000012.10:g.101770830C>T, NG_008690.1:g.69681G>A, NG_008690.2:g.110489G>A, NM_000277.2(PAH):c.735G>A (p.Val245=) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Benign BS2 [MET], BA1 [MET], BP4 [MET] The c.735G>A (p.Val245=) variant in PAH has a MAF of 0.29058 in ExAC (BA1; http://exac.broadinstitute.org) with 6,524 homozygotes (BS2). This is a synonymous variant, predicted tolerated and benign in SIFT, Polyphen. MutationTaster predicted polymorphism with no abrogation of splice sites (BP4). In summary, this variant meets criteria to be classified as benign. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-04-24 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA145982/MONDO:0009861/006 0 Benign auto Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=1 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 12 103246594 92749 G A NM_000277.1(PAH):c.841C>T (p.Pro281Ser) 92749 CA220587 NM_000277.1:c.841C>T, XM_011538422.1:c.841C>T, NM_000277.2:c.841C>T, NM_001354304.1:c.841C>T, NM_000277.3:c.841C>T, ENST00000307000.7:c.826C>T, ENST00000549247.6:n.600C>T, ENST00000553106.5:c.841C>T, ENST00000635477.1:n.2C>T, NC_000012.12:g.102852816G>A, CM000674.2:g.102852816G>A, NC_000012.11:g.103246594G>A, CM000674.1:g.103246594G>A, NC_000012.10:g.101770724G>A, NG_008690.1:g.69787C>T, NG_008690.2:g.110595C>T, NM_000277.1(PAH):c.841C>T (p.Pro281Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM2: 1 allele in ExAC ; PP3: tools predict damaging ; PP4_Moderate: P281S Identified in at least one patient with classic PKU. BH4 deficiency excluded. (PMID:15589814); PM3_Strong: Detected with c.1315+1G>A & p.Arg243Ter, pathogenic in ClinVar (PMID:26666653; PMID:27121329). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong). 15589814, 27121329, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220587/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245487 92750 C T NM_000277.2(PAH):c.890G>A (p.Arg297His) 92750 CA220590 NM_000277.2:c.890G>A, NM_000277.1:c.890G>A, XM_011538422.1:c.890G>A, NM_001354304.1:c.890G>A, NM_000277.3:c.890G>A, ENST00000307000.7:c.875G>A, ENST00000549247.6:n.649G>A, ENST00000551114.2:n.552G>A, ENST00000553106.5:c.890G>A, ENST00000635477.1:n.51G>A, NC_000012.12:g.102851709C>T, CM000674.2:g.102851709C>T, NC_000012.11:g.103245487C>T, CM000674.1:g.103245487C>T, NC_000012.10:g.101769617C>T, NG_008690.1:g.70894G>A, NG_008690.2:g.111702G>A, NM_000277.2(PAH):c.890G>A (p.Arg297His) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PS3 [MET], PM3-Strong [MET] The c.890G>A (p.Arg297His) variant in PAH has been reported in 6 patients with PKU, in trans with established pathogenic variants (PMID: 9298832,24401910) with BH4 deficiency excluded in one (PMIDs 24401910 & 9298832). This variant has an extremely low allele frequency in gnomAD (2/245792). The arginine at position 297 is in the C-terminal aromatic amino acid hydroxylase domain, and computational prediction tools and conservation analysis suggest that the c.890G>A variant may impact the protein function. Mutant enzyme activity is 20% as compared to wild type (PMID:24401910). Overall, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM2, PM3_strong, PS3. 24401910, 9298832, 24401910, 24401910, 9298832 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA220590/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 12 103245479 92751 C A NM_000277.1(PAH):c.898G>T (p.Ala300Ser) 92751 CA273108 NM_000277.1:c.898G>T, NC_000012.12:g.102851701C>A, CM000674.2:g.102851701C>A, NC_000012.11:g.103245479C>A, CM000674.1:g.103245479C>A, NC_000012.10:g.101769609C>A, NG_008690.1:g.70902G>T, NG_008690.2:g.111710G>T, XM_011538422.1:c.898G>T, NM_000277.2:c.898G>T, NM_001354304.1:c.898G>T, NM_000277.3:c.898G>T, ENST00000307000.7:c.883G>T, ENST00000549247.6:n.657G>T, ENST00000551114.2:n.560G>T, ENST00000553106.5:c.898G>T, ENST00000635477.1:n.59G>T, NM_000277.1(PAH):c.898G>T (p.Ala300Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM5 [Unmet], PM3-Very Strong [MET], PP3 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PP3: Deleterious in SIFT, Polyphen2, MutationTaster; PP4_Moderate: A300S found on 56/588 hyperphenylalaninemic patients, BH4 deficiency excluded. Upgraded per ClinGen Metabolic WG. (PMID:21147011); PM3_VeryStrong: Detected with c.1066-11G>A (P), R261Q(P/LP), L48S (P), R176X (P) in 20 patients. (PMID:21147011); PS3: A300S in vitro PAH activity of 31% (PMID:17935162). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PP4_Moderate, PM3_VeryStrong, PS3). 21147011, 21147011, 17935162 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273108/MONDO:0009861/006 0.3246 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245464 92752 C T NM_000277.2(PAH):c.912+1G>A 92752 CA220591 NM_000277.2:c.912+1G>A, NM_000277.1:c.912+1G>A, XM_011538422.1:c.912+1G>A, NM_001354304.1:c.912+1G>A, NM_000277.3:c.912+1G>A, ENST00000307000.7:c.897+1G>A, ENST00000549247.6:n.671+1G>A, ENST00000551114.2:n.574+1G>A, ENST00000553106.5:c.912+1G>A, ENST00000635477.1:n.73+1G>A, NC_000012.12:g.102851686C>T, CM000674.2:g.102851686C>T, NC_000012.11:g.103245464C>T, CM000674.1:g.103245464C>T, NC_000012.10:g.101769594C>T, NG_008690.1:g.70917G>A, NG_008690.2:g.111725G>A, NM_000277.2(PAH):c.912+1G>A PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00006.; PVS1: Canonical +1 splice site; PP4: Detected in 5 patients with classical PKU. (PMID:8659548). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4). 8659548 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220591/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103240716 92753 G A NM_000277.1(PAH):c.926C>T (p.Ala309Val) 92753 CA220592 NM_000277.1:c.926C>T, XM_011538422.1:c.913-2507C>T, NM_000277.2:c.926C>T, NM_001354304.1:c.926C>T, NM_000277.3:c.926C>T, ENST00000307000.7:c.911C>T, ENST00000549247.6:n.685C>T, ENST00000551114.2:n.588C>T, ENST00000553106.5:c.926C>T, ENST00000635477.1:n.74-2507C>T, ENST00000635528.1:n.441C>T, NC_000012.12:g.102846938G>A, CM000674.2:g.102846938G>A, NC_000012.11:g.103240716G>A, CM000674.1:g.103240716G>A, NC_000012.10:g.101764846G>A, NG_008690.1:g.75665C>T, NG_008690.2:g.116473C>T, NM_000277.1(PAH):c.926C>T (p.Ala309Val) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PM3 [MET], PP3 [MET], PP4 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Low frequency. 1.0e-5; PP3: All databases agree on damaging effect. REVEL=0.921; PS3: Enzyme activity = 30% (Ho, 2008) (PMID:18590700); PM3: Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T (PMID:26666653); PP4: Single patient with classic PKU (>1200umol/L), BH4 defect not excluded (PMID:26666653). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4). 26666653, 26666653, 18590700 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220592/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103240630 92755 C A NM_000277.2(PAH):c.969+43G>T 92755 CA145984 NM_000277.2:c.969+43G>T, NM_000277.1:c.969+43G>T, XM_011538422.1:c.913-2421G>T, NM_001354304.1:c.969+43G>T, NM_000277.3:c.969+43G>T, ENST00000307000.7:c.954+43G>T, ENST00000549247.6:n.728+43G>T, ENST00000551114.2:n.631+43G>T, ENST00000553106.5:c.969+43G>T, ENST00000635477.1:n.74-2421G>T, ENST00000635528.1:n.484+43G>T, NC_000012.12:g.102846852C>A, CM000674.2:g.102846852C>A, NC_000012.11:g.103240630C>A, CM000674.1:g.103240630C>A, NC_000012.10:g.101764760C>A, NG_008690.1:g.75751G>T, NG_008690.2:g.116559G>T, NM_000277.2(PAH):c.969+43G>T PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Benign BP4 [Unmet], BA1 [MET] PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.49022 in ExAC. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA145984/MONDO:0009861/006 0 Benign auto Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=1 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89624218 92808 C G NM_000314.6(PTEN):c.-9C>G 92808 CA000663 NM_000314.6:c.-9C>G, NC_000010.11:g.87864461C>G, CM000672.2:g.87864461C>G, NC_000010.10:g.89624218C>G, CM000672.1:g.89624218C>G, NC_000010.9:g.89614198C>G, NG_007466.2:g.6023C>G, LRG_311:g.6023C>G, NG_033079.1:g.3977G>C, NM_000314.5:c.-9C>G, NM_001304717.2:c.511C>G, NM_001304718.1:c.-714C>G, XM_006717926.2:c.-9C>G, XM_011539981.1:c.-9C>G, XR_945789.1:n.704C>G, XR_945790.1:n.704C>G, XR_945791.1:n.704C>G, NM_000314.7:c.-9C>G, NM_001304717.5:c.511C>G, NM_001304718.2:c.-714C>G, ENST00000371953.7:c.-9C>G, ENST00000487939.1:n.13C>G, ENST00000610634.1:c.-111C>G, NM_000314.6(PTEN):c.-9C>G PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Benign BA1 [MET] PTEN c.-9C>G (NC_000010.10:g.89624218C>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.048 (4.8%, 903/18,870 alleles) in the East Asian subpopulation of the gnomAD cohort. (PMID 27535533) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-11-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000663/MONDO:0017623/003 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 10 89720907 92810 T G NM_000314.6(PTEN):c.1026+32T>G 92810 CA000255 NM_000314.6:c.1026+32T>G, NC_000010.11:g.87961150T>G, CM000672.2:g.87961150T>G, NC_000010.10:g.89720907T>G, CM000672.1:g.89720907T>G, NC_000010.9:g.89710887T>G, NG_007466.2:g.102712T>G, LRG_311:g.102712T>G, NM_000314.5:c.1026+32T>G, NM_001304717.2:c.1545+32T>G, NM_001304718.1:c.435+32T>G, XM_006717926.2:c.981+32T>G, XM_011539981.1:c.1026+32T>G, XM_011539982.1:c.930+32T>G, XR_945791.1:n.1596+32T>G, NM_000314.7:c.1026+32T>G, NM_001304717.5:c.1545+32T>G, NM_001304718.2:c.435+32T>G, ENST00000371953.7:c.1026+32T>G, ENST00000472832.2:n.485T>G, NM_000314.6(PTEN):c.1026+32T>G PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Benign BA1 [MET] PTEN c.1026+32T>G (IVS8+32T>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.374 (37.4%, 102,771/274,696 alleles) in the gnomAD cohort. (PMID 27535533) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000255/MONDO:0017623/003 0 Benign auto Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=1 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89653834 92813 C T NM_000314.6(PTEN):c.132C>T (p.Gly44=) 92813 CA000318 NM_000314.6:c.132C>T, NM_000314.5:c.132C>T, NM_001304717.2:c.651C>T, NM_001304718.1:c.-574C>T, XM_006717926.2:c.132C>T, XM_011539981.1:c.132C>T, XM_011539982.1:c.68+13639C>T, XR_945789.1:n.844C>T, XR_945790.1:n.844C>T, XR_945791.1:n.844C>T, NM_000314.7:c.132C>T, NM_001304717.5:c.651C>T, NM_001304718.2:c.-574C>T, ENST00000371953.7:c.132C>T, ENST00000462694.1:n.134C>T, ENST00000610634.1:c.30C>T, NC_000010.11:g.87894077C>T, CM000672.2:g.87894077C>T, NC_000010.10:g.89653834C>T, CM000672.1:g.89653834C>T, NC_000010.9:g.89643814C>T, NG_007466.2:g.35639C>T, LRG_311:g.35639C>T, NM_000314.6(PTEN):c.132C>T (p.Gly44=) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign BP5 [MET], BP7 [MET], BS1 [MET], BS2-Supporting [MET] PTEN c.132C>T (p.G44=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.167 (1.67%, 463/276,792 alleles) in the gnomAD cohort. (PMID 27535533)BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (Internal laboratory contributor(s) SCV000212700.3)BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributor(s) SCV000212700.3)BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-11-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000318/MONDO:0017623/003 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 89685314 92816 TGTAA T NM_000314.6(PTEN):c.209+4_209+7delAGTA 92816 CA220637 NM_000314.6:c.209+4_209+7delAGTA, NC_000010.11:g.87925561_87925564del, CM000672.2:g.87925561_87925564del, NC_000010.10:g.89685318_89685321del, CM000672.1:g.89685318_89685321del, NC_000010.9:g.89675298_89675301del, NG_007466.2:g.67123_67126del, LRG_311:g.67123_67126del, NM_000314.5:c.209+4_209+7del, NM_000314.6:c.209+4_209+7del, NM_001304717.2:c.728+4_728+7del, NM_001304718.1:c.-541-5485_-541-5482del, XM_006717926.2:c.165-5485_165-5482del, XM_011539981.1:c.209+4_209+7del, XM_011539982.1:c.113+4_113+7del, XR_945789.1:n.921+4_921+7del, XR_945790.1:n.921+4_921+7del, XR_945791.1:n.921+4_921+7del, NM_000314.7:c.209+4_209+7del, NM_001304717.5:c.728+4_728+7del, NM_001304718.2:c.-541-5485_-541-5482del, ENST00000371953.7:c.209+4_209+7del, ENST00000498703.1:n.35+4_35+7del, ENST00000610634.1:c.107+4_107+7del, NM_000314.6(PTEN):c.209+4_209+7delAGTA PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PS4-Supporting [MET], PM6-Strong [MET], PS3 [MET], PP1-Moderate [MET] PTEN c.209+4_209+7delAGTA (IVS3+4_IVS3+7delAGTA) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: RNA, mini-gene, or other assay shows impact on splicing. (PMID 28677221)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (Internal laboratory contributor(s))PM2: Absent in large sequenced populations (PMID 27535533).PP1_M: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (Internal laboratory contributor(s))PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221, internal laboratory contributor(s) SCV000273868.4) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-12-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA220637/MONDO:0017623/003 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692731 92818 G T NM_000314.6(PTEN):c.254-39G>T 92818 CA000368 NM_000314.6:c.254-39G>T, NC_000010.11:g.87932974G>T, CM000672.2:g.87932974G>T, NC_000010.10:g.89692731G>T, CM000672.1:g.89692731G>T, NC_000010.9:g.89682711G>T, NG_007466.2:g.74536G>T, LRG_311:g.74536G>T, NM_000314.5:c.254-39G>T, NM_001304717.2:c.773-39G>T, NM_001304718.1:c.-497-39G>T, XM_006717926.2:c.209-39G>T, XM_011539981.1:c.254-39G>T, XM_011539982.1:c.158-39G>T, XR_945789.1:n.966-39G>T, XR_945790.1:n.966-39G>T, XR_945791.1:n.966-39G>T, NM_000314.7:c.254-39G>T, NM_001304717.5:c.773-39G>T, NM_001304718.2:c.-497-39G>T, ENST00000371953.7:c.254-39G>T, ENST00000498703.1:n.80-39G>T, ENST00000610634.1:c.152-39G>T, NM_000314.6(PTEN):c.254-39G>T PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign BP4 [MET], BP7 [MET], BS1 [MET] PTEN c.254-39G>T (IVS4-39G>T) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0064 (0.64%, 112/17,490 alleles) in the South Asian subpopulation of the gnomAD cohort. (PMID 27535533)BP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is intronic and at or beyond +7/-21, nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-12-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000368/MONDO:0017623/003 0.0028 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89692847 92820 T C NM_000314.6(PTEN):c.331T>C (p.Trp111Arg) 92820 CA000401 NM_000314.6:c.331T>C, NM_000314.5:c.331T>C, NM_001304717.2:c.850T>C, NM_001304718.1:c.-420T>C, XM_006717926.2:c.286T>C, XM_011539981.1:c.331T>C, XM_011539982.1:c.235T>C, XR_945789.1:n.1043T>C, XR_945790.1:n.1043T>C, XR_945791.1:n.1043T>C, NM_000314.7:c.331T>C, NM_001304717.5:c.850T>C, NM_001304718.2:c.-420T>C, ENST00000371953.7:c.331T>C, ENST00000498703.1:n.157T>C, ENST00000610634.1:c.229T>C, NC_000010.11:g.87933090T>C, CM000672.2:g.87933090T>C, NC_000010.10:g.89692847T>C, CM000672.1:g.89692847T>C, NC_000010.9:g.89682827T>C, NG_007466.2:g.74652T>C, LRG_311:g.74652T>C, NM_000314.6(PTEN):c.331T>C (p.Trp111Arg) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS3 [MET], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet] PTEN c.331T>C (p.W111R) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29785012, 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 11476841, 29785012, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-11-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000401/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 10 89692911 92822 G A NM_000314.6(PTEN):c.395G>A (p.Gly132Asp) 92822 CA000444 NM_000314.6:c.395G>A, NC_000010.11:g.87933154G>A, CM000672.2:g.87933154G>A, NC_000010.10:g.89692911G>A, CM000672.1:g.89692911G>A, NC_000010.9:g.89682891G>A, NG_007466.2:g.74716G>A, LRG_311:g.74716G>A, NM_000314.5:c.395G>A, NM_001304717.2:c.914G>A, NM_001304718.1:c.-356G>A, XM_006717926.2:c.350G>A, XM_011539981.1:c.395G>A, XM_011539982.1:c.299G>A, XR_945789.1:n.1107G>A, XR_945790.1:n.1107G>A, XR_945791.1:n.1107G>A, NM_000314.7:c.395G>A, NM_001304717.5:c.914G>A, NM_001304718.2:c.-356G>A, ENST00000371953.7:c.395G>A, ENST00000498703.1:n.221G>A, ENST00000610634.1:c.293G>A, NM_000314.6(PTEN):c.395G>A (p.Gly132Asp) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [MET], PP2 [MET], PS4-Moderate [MET] PTEN c.395G>A (p.G132D) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000279163.8)PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 25288137, PMID 23335809, PMID 23470840, internal laboratory contributor(s))PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 23335809, 23470840, 25288137 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000444/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 5 Likely Pathogenic 10 89624340 92827 C T NM_000314.6(PTEN):c.79+35C>T 92827 CA000576 NM_000314.6:c.79+35C>T, NC_000010.11:g.87864583C>T, CM000672.2:g.87864583C>T, NC_000010.10:g.89624340C>T, CM000672.1:g.89624340C>T, NC_000010.9:g.89614320C>T, NG_007466.2:g.6145C>T, LRG_311:g.6145C>T, NG_033079.1:g.3855G>A, NM_000314.5:c.79+35C>T, NM_001304717.2:c.598+35C>T, NM_001304718.1:c.-627+35C>T, XM_006717926.2:c.79+35C>T, XM_011539981.1:c.79+35C>T, XR_945789.1:n.791+35C>T, XR_945790.1:n.791+35C>T, XR_945791.1:n.791+35C>T, NM_000314.7:c.79+35C>T, NM_001304717.5:c.598+35C>T, NM_001304718.2:c.-627+35C>T, ENST00000371953.7:c.79+35C>T, ENST00000462694.1:n.81+35C>T, ENST00000487939.1:n.100+35C>T, ENST00000610634.1:c.-24+35C>T, ENST00000618586.1:n.83C>T, NM_000314.6(PTEN):c.79+35C>T PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Benign BS1 [MET], BS3 [MET] PTEN c.79+35C>T (IVS1+35C>T) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.00178 (1.78%, 492/277,200 alleles) in the gnomAD cohort. (PMID 27535533) BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 17636424) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000576/MONDO:0017623/003 0.0507 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89717799 92829 G A NM_000314.6(PTEN):c.801+23G>A 92829 CA000585 NM_000314.6:c.801+23G>A, NM_000314.5:c.801+23G>A, NM_001304717.2:c.1320+23G>A, NM_001304718.1:c.210+23G>A, XM_006717926.2:c.756+23G>A, XM_011539981.1:c.801+23G>A, XM_011539982.1:c.705+23G>A, XR_945791.1:n.1371+23G>A, NM_000314.7:c.801+23G>A, NM_001304717.5:c.1320+23G>A, NM_001304718.2:c.210+23G>A, ENST00000371953.7:c.801+23G>A, ENST00000472832.2:n.228+23G>A, NC_000010.11:g.87958042G>A, CM000672.2:g.87958042G>A, NC_000010.10:g.89717799G>A, CM000672.1:g.89717799G>A, NC_000010.9:g.89707779G>A, NG_007466.2:g.99604G>A, LRG_311:g.99604G>A, NM_000314.6(PTEN):c.801+23G>A PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign BP4 [MET], BS1 [MET] PTEN c.801+23G>A (IVS7+23G>A) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0024 (0.24%, 58/24,016 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533)BP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-09-26 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000585/MONDO:0017623/003 0.0507 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 15 66777315 94082 G GTC NM_002755.3(MAP2K1):c.694-8_694-7dupTC 94082 CA147595 NM_002755.3:c.694-7_694-6insTC, NM_002755.3:c.694-8_694-7dupTC, NM_002755.3:c.694-8_694-7dup, LRG_725t1:c.694-8_694-7dup, XM_011521783.1:c.628-8_628-7dup, XM_011521783.3:c.628-8_628-7dup, XM_017022411.2:c.616-8_616-7dup, XM_017022412.1:c.550-8_550-7dup, XM_017022413.1:c.166-8_166-7dup, ENST00000307102.9:c.694-8_694-7dup, ENST00000566326.1:c.166-8_166-7dup, NC_000015.10:g.66484982_66484983dup, CM000677.2:g.66484982_66484983dup, NC_000015.9:g.66777320_66777321dup, CM000677.1:g.66777320_66777321dup, NC_000015.8:g.64564374_64564375dup, NG_008305.1:g.103110_103111dup, LRG_725:g.103110_103111dup, NM_002755.3(MAP2K1):c.694-8_694-7dupTC MAP2K1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BP5 [MET], BA1 [MET] The filtering allele frequency of the c.694-8_694-7dupTC variant in the MAP2K1 gene is 4.97% for African chromosomes by the Exome Aggregation Consortium (515/10368 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL genetics internal data 26957, 21766, 500060; ClinVar SCV000111925.5; SCV000204171.4; SCV000207934.6). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA147595/MONDO:0021060/004 0.0003 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 12 103238154 102475 GC G NM_000277.2(PAH):c.1024delG (p.Ala342Hisfs) 102475 CA229279 NM_000277.2:c.1024delG, NC_000012.12:g.102844378del, CM000674.2:g.102844378del, NC_000012.11:g.103238156del, CM000674.1:g.103238156del, NC_000012.10:g.101762286del, NG_008690.1:g.78226del, NG_008690.2:g.119034del, NM_000277.1:c.1024del, XM_011538422.1:c.967del, NM_000277.2:c.1024del, NM_001354304.1:c.1024del, NM_000277.3:c.1024del, ENST00000307000.7:c.1009del, ENST00000549247.6:n.783del, ENST00000551114.2:n.686del, ENST00000553106.5:c.1024del, ENST00000635477.1:n.128del, ENST00000635528.1:n.539del, NM_000277.2(PAH):c.1024delG (p.Ala342Hisfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4-Moderate [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PVS1: Frameshift variant; PP4_Moderate: Reported in patients with PAH deficiency. Bh4 defects excluded. (PMID:9634518). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4_Moderate). 9634518 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229279/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103238146 102483 C T NM_000277.2(PAH):c.1033G>A (p.Ala345Thr) 102483 CA229291 NM_000277.2:c.1033G>A, NM_000277.1:c.1033G>A, XM_011538422.1:c.976G>A, NM_001354304.1:c.1033G>A, NM_000277.3:c.1033G>A, ENST00000307000.7:c.1018G>A, ENST00000549247.6:n.792G>A, ENST00000551114.2:n.695G>A, ENST00000553106.5:c.1033G>A, ENST00000635477.1:n.137G>A, ENST00000635528.1:n.548G>A, NC_000012.12:g.102844368C>T, CM000674.2:g.102844368C>T, NC_000012.11:g.103238146C>T, CM000674.1:g.103238146C>T, NC_000012.10:g.101762276C>T, NG_008690.1:g.78235G>A, NG_008690.2:g.119043G>A, NM_000277.2(PAH):c.1033G>A (p.Ala345Thr) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [MET], PM3 [MET], PP3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from controls in ExaC, 100 Genomes, ESP, and gnomAD; PP3: Deleterious effected predicted by SIFT, Polyphen2, and MutationTaster; PM5: A345S (Variant ID 102484) predicted pathogenic in ClinVar; PP4_Moderate: Found in two individuals with Classic PKU on exon 10.Urinary pterin analysis and dihydropteridine reductase (DHPR) assay were performed t (PMID:15503242); PM3: Found in trans with R243Q (pathogenic in ClinVar). (PMID:15503242). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM5, PP4_Moderate, PM3). 15503242, 15503242 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229291/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103238123 102498 AC A NM_000277.2(PAH):c.1055delG (p.Gly352Valfs) 102498 CA229311 NM_000277.2:c.1055delG, NM_000277.1:c.1055del, XM_011538422.1:c.998del, NM_000277.2:c.1055del, NM_001354304.1:c.1055del, NM_000277.3:c.1055del, ENST00000307000.7:c.1040del, ENST00000549247.6:n.814del, ENST00000551114.2:n.717del, ENST00000553106.5:c.1055del, ENST00000635477.1:n.159del, ENST00000635528.1:n.570del, NC_000012.12:g.102844347del, CM000674.2:g.102844347del, NC_000012.11:g.103238125del, CM000674.1:g.103238125del, NC_000012.10:g.101762255del, NG_008690.1:g.78257del, NG_008690.2:g.119065del, NM_000277.2(PAH):c.1055delG (p.Gly352Valfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency in ExAC, MAF=0.00002.; PP4: Identified in a pair of siblings with PKU. (PMID:7913581). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4). 7913581 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229311/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237533 102518 GC G NM_000277.2(PAH):c.1089delG (p.Lys363Asnfs) 102518 CA229336 NM_000277.2:c.1089delG, NC_000012.12:g.102843756del, CM000674.2:g.102843756del, NC_000012.11:g.103237534del, CM000674.1:g.103237534del, NC_000012.10:g.101761664del, NG_008690.1:g.78847del, NG_008690.2:g.119655del, NM_000277.1:c.1089del, XM_011538422.1:c.1032del, NM_000277.2:c.1089del, NM_001354304.1:c.1089del, NM_000277.3:c.1089del, ENST00000307000.7:c.1074del, ENST00000549247.6:n.848del, ENST00000551114.2:n.751del, ENST00000553106.5:c.1089del, ENST00000635477.1:n.193del, ENST00000635528.1:n.604del, NM_000277.2(PAH):c.1089delG (p.Lys363Asnfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PVS1 [MET], PM2 [MET], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4: Detected in a patient with Classical PKU. (PMID:8659548). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4). 8659548 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229336/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237523 102525 A G NM_000277.2(PAH):c.1100T>C (p.Leu367Pro) 102525 CA229344 NM_000277.2:c.1100T>C, NM_000277.1:c.1100T>C, XM_011538422.1:c.1043T>C, NM_001354304.1:c.1100T>C, NM_000277.3:c.1100T>C, ENST00000307000.7:c.1085T>C, ENST00000549247.6:n.859T>C, ENST00000551114.2:n.762T>C, ENST00000553106.5:c.1100T>C, ENST00000635477.1:n.204T>C, ENST00000635528.1:n.615T>C, NC_000012.12:g.102843745A>G, CM000674.2:g.102843745A>G, NC_000012.11:g.103237523A>G, CM000674.1:g.103237523A>G, NC_000012.10:g.101761653A>G, NG_008690.1:g.78858T>C, NG_008690.2:g.119666T>C, NM_000277.2(PAH):c.1100T>C (p.Leu367Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PP3 [MET] The c.1100T>C (p.Leu367Pro) variant in PAH is reported in a Japanese patient with PKU, BH4 deficiency was excluded. (PMID: 21307867) This variant is absent in population databases. It is predicted deleterious by SIFT, Polyphen-2 and MutationTaster. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. 21307867 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-08 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229344/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237522 102526 C T NM_000277.2(PAH):c.1101G>A (p.Leu367=) 102526 CA229346 NM_000277.2:c.1101G>A, NM_000277.1:c.1101G>A, XM_011538422.1:c.1044G>A, NM_001354304.1:c.1101G>A, NM_000277.3:c.1101G>A, ENST00000307000.7:c.1086G>A, ENST00000549247.6:n.860G>A, ENST00000551114.2:n.763G>A, ENST00000553106.5:c.1101G>A, ENST00000635477.1:n.205G>A, ENST00000635528.1:n.616G>A, NC_000012.12:g.102843744C>T, CM000674.2:g.102843744C>T, NC_000012.11:g.103237522C>T, CM000674.1:g.103237522C>T, NC_000012.10:g.101761652C>T, NG_008690.1:g.78859G>A, NG_008690.2:g.119667G>A, NM_000277.2(PAH):c.1101G>A (p.Leu367=) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM3 [MET], PP3 [MET], PP4 [MET] The c.1101G>A (p.Leu367=) variant in PAH is reported in an individual with Classic PKU, in trans with p.R243Q. (PMID: 16256386) This variant is absent in population databases. Two splicing algorthms predict a deleterious effect (Human splicing finder: potential alteration of splicing; MaxEnt scan: +571.94% Variation). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4, PP3. 16256386, 16256386 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-08 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229346/MONDO:0009861/006 0.3246 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 12 103306625 102531 T TC NM_000277.1(PAH):c.111_112insG (p.Ile38Aspfs) 102531 CA229354 NM_000277.1:c.111_112insG, NM_000277.1:c.111dup, XM_011538422.1:c.111dup, NM_000277.2:c.111dup, NM_001354304.1:c.111dup, XM_017019370.2:c.111dup, NM_000277.3:c.111dup, ENST00000307000.7:c.96dup, ENST00000546844.1:c.111dup, ENST00000548677.2:n.198dup, ENST00000548928.1:n.33dup, ENST00000549111.5:n.207dup, ENST00000550978.6:n.95dup, ENST00000551337.5:c.111dup, ENST00000551988.5:n.200dup, ENST00000553106.5:c.111dup, ENST00000635500.1:n.79dup, NC_000012.12:g.102912848dup, CM000674.2:g.102912848dup, NC_000012.11:g.103306626dup, CM000674.1:g.103306626dup, NC_000012.10:g.101830756dup, NG_008690.1:g.9755dup, NG_008690.2:g.50563dup, NM_000277.1(PAH):c.111_112insG (p.Ile38Aspfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] The c.112dupG variant in PAH has been previously reported as a single variant (no second mutation detected) in 1 Chinese patient with classic PKU (PMID: 16256386); BH4 deficiency was not excluded (PP4). The variant is a frameshift variant occurring in exon 2 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2. 16256386 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229354/MONDO:0009861/006 0.9941 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237423 102557 C G NM_000277.2(PAH):c.1199+1G>C 102557 CA274088 NM_000277.2:c.1199+1G>C, NC_000012.12:g.102843645C>G, CM000674.2:g.102843645C>G, NC_000012.11:g.103237423C>G, CM000674.1:g.103237423C>G, NC_000012.10:g.101761553C>G, NG_008690.1:g.78958G>C, NG_008690.2:g.119766G>C, NM_000277.1:c.1199+1G>C, XM_011538422.1:c.1142+1G>C, NM_001354304.1:c.1199+1G>C, NM_000277.3:c.1199+1G>C, ENST00000307000.7:c.1184+1G>C, ENST00000549247.6:n.958+1G>C, ENST00000551114.2:n.861+1G>C, ENST00000553106.5:c.1199+1G>C, ENST00000635477.1:n.303+1G>C, ENST00000635528.1:n.714+1G>C, NM_000277.2(PAH):c.1199+1G>C PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4-Moderate [MET], PM3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: 8.1e-6 allele frequency in GnomAD, not found in any other databases; PM3: [c.898G>T];[c.1199+1G>C] in a patient with mild hyperphe (180umol/L); PP4_Moderate: Single patient in Sterl 2013, BH4 defect excluded. Also identified in multiple other patients (7 publications linked through ClinVar) (PMID:22526846); PVS1: +1 canonical splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM3, PP4_Moderate, PVS1). 22526846 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-27 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA274088/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234276 102567 A G NM_000277.2(PAH):c.1217T>C (p.Ile406Thr) 102567 CA229398 NM_000277.2:c.1217T>C, NM_000277.1:c.1217T>C, XM_011538422.1:c.1160T>C, NM_001354304.1:c.1217T>C, NM_000277.3:c.1217T>C, ENST00000307000.7:c.1202T>C, ENST00000551114.2:n.879T>C, ENST00000553106.5:c.1217T>C, ENST00000635477.1:n.321T>C, ENST00000635528.1:n.732T>C, NC_000012.12:g.102840498A>G, CM000674.2:g.102840498A>G, NC_000012.11:g.103234276A>G, CM000674.1:g.103234276A>G, NC_000012.10:g.101758406A>G, NG_008690.1:g.82105T>C, NG_008690.2:g.122913T>C, NM_000277.2(PAH):c.1217T>C (p.Ile406Thr) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET] The c.1217T>C (p.Ile406Thr) variant in PAH is reported in 2 unrelated patients with PKU; BH4 cofactor deficiency was ruled out. (PMID: 10234516, 27121329, 28754886) This variant was reported in trans with known pathogenic variants p.I65T (PMID: 10234516) and IVS4-1G>A (PMID: 28754886). It is absent in population databases, and multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3. 27121329, 10234516, 28754886, 10234516 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229398/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234251 102577 G A NM_000277.2(PAH):c.1242C>T (p.Tyr414=) 102577 CA200893 NM_000277.2:c.1242C>T, NM_000277.1:c.1242C>T, XM_011538422.1:c.1185C>T, NM_001354304.1:c.1242C>T, NM_000277.3:c.1242C>T, ENST00000307000.7:c.1227C>T, ENST00000551114.2:n.904C>T, ENST00000553106.5:c.1242C>T, ENST00000635477.1:n.346C>T, ENST00000635528.1:n.757C>T, NC_000012.12:g.102840473G>A, CM000674.2:g.102840473G>A, NC_000012.11:g.103234251G>A, CM000674.1:g.103234251G>A, NC_000012.10:g.101758381G>A, NG_008690.1:g.82130C>T, NG_008690.2:g.122938C>T, NM_000277.2(PAH):c.1242C>T (p.Tyr414=) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Benign BS1 [MET], BS2 [MET], BP4 [Unmet] PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01361 in ENF from gnomAD; BS2: 19 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BS2). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA200893/MONDO:0009861/006 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 12 103306612 102581 T A NM_000277.2(PAH):c.125A>T (p.Lys42Ile) 102581 CA229419 NM_000277.2:c.125A>T, NM_000277.1:c.125A>T, XM_011538422.1:c.125A>T, NM_001354304.1:c.125A>T, XM_017019370.2:c.125A>T, NM_000277.3:c.125A>T, ENST00000307000.7:c.110A>T, ENST00000546844.1:c.125A>T, ENST00000548677.2:n.212A>T, ENST00000548928.1:n.47A>T, ENST00000549111.5:n.221A>T, ENST00000550978.6:n.109A>T, ENST00000551337.5:c.125A>T, ENST00000551988.5:n.214A>T, ENST00000553106.5:c.125A>T, ENST00000635500.1:n.93A>T, NC_000012.12:g.102912834T>A, CM000674.2:g.102912834T>A, NC_000012.11:g.103306612T>A, CM000674.1:g.103306612T>A, NC_000012.10:g.101830742T>A, NG_008690.1:g.9769A>T, NG_008690.2:g.50577A>T, NM_000277.2(PAH):c.125A>T (p.Lys42Ile) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM3 [MET], PP3 [Unmet], PP4 [MET], PS3 [MET] The c.125A>T (p.Lys42Ile) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency not assessed/reported). (PP4; PMID: 9380432; 9781015). This variant is absent in population databases (PM2). This variant was detected with p.E280K (Pathogenic in ClinVar) (PM3). This variant has 12% enzyme activity in vitro (PS3; PMID: 21953985). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PP4, PM2, PM3. 9380432, 9380432, 9781015, 21953985, 11461190 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229419/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234222 102584 A G NM_000277.2(PAH):c.1271T>C (p.Leu424Ser) 102584 CA229424 NM_000277.2:c.1271T>C, NM_000277.1:c.1271T>C, XM_011538422.1:c.1214T>C, NM_001354304.1:c.1271T>C, NM_000277.3:c.1271T>C, ENST00000307000.7:c.1256T>C, ENST00000551114.2:n.933T>C, ENST00000553106.5:c.1271T>C, ENST00000635477.1:n.375T>C, ENST00000635528.1:n.786T>C, NC_000012.12:g.102840444A>G, CM000674.2:g.102840444A>G, NC_000012.11:g.103234222A>G, CM000674.1:g.103234222A>G, NC_000012.10:g.101758352A>G, NG_008690.1:g.82159T>C, NG_008690.2:g.122967T>C, NM_000277.2(PAH):c.1271T>C (p.Leu424Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], BS1 [Unmet], PM5 [Unmet], PP3 [MET], BS2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet] The NM_000277.2:c.1271T>C (p.Leu424Ser) variant in PAH has not been reported in the medical literature. This variant is absent from 1000G, ESP, ExAC, and gnomAD. A deleterious effect is predicted in SIFT, Polyphen-2, and REVEL=0.966. Overall, there is not enough evidence to classify the p.Leu424Ser variant with certainty. PAH-specific ACMG/AMP criteria applied: PM2, PP3. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229424/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234176 102588 A G NM_000277.2(PAH):c.1315+2T>C 102588 CA229429 NM_000277.2:c.1315+2T>C, NM_000277.1:c.1315+2T>C, XM_011538422.1:c.1258+2T>C, NM_001354304.1:c.1315+2T>C, NM_000277.3:c.1315+2T>C, ENST00000307000.7:c.1300+2T>C, ENST00000551114.2:n.977+2T>C, ENST00000553106.5:c.1315+2T>C, ENST00000635477.1:n.419+2T>C, ENST00000635528.1:n.830+2T>C, NC_000012.12:g.102840398A>G, CM000674.2:g.102840398A>G, NC_000012.11:g.103234176A>G, CM000674.1:g.103234176A>G, NC_000012.10:g.101758306A>G, NG_008690.1:g.82205T>C, NG_008690.2:g.123013T>C, NM_000277.2(PAH):c.1315+2T>C PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [Unmet], PM3-Strong [MET] The c.1315+2T>C variant is at the 3' canonical splice site in the penultimate exon of PAH. It is absent form population databases and has been identified in trans with pathogenic variants in three independent patients (F39del, Y414C, and R261X; PMID: 9452062; 9521426). A defect of BH4 metabolism was excluded as a cause of elevated phenylalanine in all patients. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. 9521426, 9521426, 9452062 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229429/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103306599 102597 AC A NM_000277.2(PAH):c.137delG (p.Gly46Valfs) 102597 CA229440 NC_000012.12:g.102912823del, CM000674.2:g.102912823del, NC_000012.11:g.103306601del, CM000674.1:g.103306601del, NC_000012.10:g.101830731del, NG_008690.1:g.9781del, NG_008690.2:g.50589del, NM_000277.1:c.137del, XM_011538422.1:c.137del, NM_000277.2:c.137del, NM_001354304.1:c.137del, XM_017019370.2:c.137del, NM_000277.3:c.137del, ENST00000307000.7:c.122del, ENST00000546844.1:c.137del, ENST00000548677.2:n.224del, ENST00000548928.1:n.59del, ENST00000549111.5:n.233del, ENST00000550978.6:n.121del, ENST00000551337.5:c.137del, ENST00000551988.5:n.226del, ENST00000553106.5:c.137del, ENST00000635500.1:n.105del, NM_000277.2(PAH):c.137delG (p.Gly46Valfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] The c.137delG (p.Gly46Vfs*15) is a frameshift in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in 1 individual with PKU (BH4 deficiency not excluded), who carried a second splicing variant (PP4; PMID: 10196714 ). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. 10196714 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229440/MONDO:0009861/006 0.9941 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103306579 102601 C T NM_000277.2(PAH):c.158G>A (p.Arg53His) 102601 CA229447 NM_000277.2:c.158G>A, NC_000012.12:g.102912801C>T, CM000674.2:g.102912801C>T, NC_000012.11:g.103306579C>T, CM000674.1:g.103306579C>T, NC_000012.10:g.101830709C>T, NG_008690.1:g.9802G>A, NG_008690.2:g.50610G>A, NM_000277.1:c.158G>A, XM_011538422.1:c.158G>A, NM_001354304.1:c.158G>A, XM_017019370.2:c.158G>A, NM_000277.3:c.158G>A, ENST00000307000.7:c.143G>A, ENST00000546844.1:c.158G>A, ENST00000548677.2:n.245G>A, ENST00000548928.1:n.80G>A, ENST00000549111.5:n.254G>A, ENST00000550978.6:n.142G>A, ENST00000551337.5:c.158G>A, ENST00000551988.5:n.247G>A, ENST00000553106.5:c.158G>A, ENST00000635500.1:n.126G>A, NM_000277.2(PAH):c.158G>A (p.Arg53His) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance BS1 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [Unmet] PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes); PP4_moderate: Detected in multiple patients with hyperphenylalaninemia, BH4 deficiency excluded (PMID:24401910, 26322415); PM3: Detected in trans with pathogenic variant p.R243Q. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, PP4_moderate, PM3). 24401910, 26322415, 24401910, 26322415 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229447/MONDO:0009861/006 0.3246 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103306568 102604 C T NM_000277.2(PAH):c.168+1G>A 102604 CA229452 NM_000277.2:c.168+1G>A, NM_000277.1:c.168+1G>A, XM_011538422.1:c.168+1G>A, NM_001354304.1:c.168+1G>A, XM_017019370.2:c.168+1G>A, NM_000277.3:c.168+1G>A, ENST00000307000.7:c.153+1G>A, ENST00000546844.1:c.168+1G>A, ENST00000548677.2:n.255+1G>A, ENST00000548928.1:n.90+1G>A, ENST00000549111.5:n.264+1G>A, ENST00000550978.6:n.152+1G>A, ENST00000551337.5:c.168+1G>A, ENST00000551988.5:n.257+1G>A, ENST00000553106.5:c.168+1G>A, ENST00000635500.1:n.136+1G>A, NC_000012.12:g.102912790C>T, CM000674.2:g.102912790C>T, NC_000012.11:g.103306568C>T, CM000674.1:g.103306568C>T, NC_000012.10:g.101830698C>T, NG_008690.1:g.9813G>A, NG_008690.2:g.50621G>A, NM_000277.2(PAH):c.168+1G>A PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PVS1 [MET], PM3 [MET] The c.168+1G>A variant in PAH is at a canonical splice site at intron 3, and is absent in all population databases. It has been identified in trans with a pathogenic variant (Ho, 2014), and as a homozygous variant (PMID: 18294361) in patients with phenylketonuria. Defects in BH4 metabolism were excluded as a cause of elevated phenylalanine in two patients (PMID: 24368688, 8807331). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate. 24368688, 8807331, 24368688, 18294361 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229452/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103306564 102605 C T NM_000277.2(PAH):c.168+5G>A 102605 CA229453 NM_000277.2:c.168+5G>A, NM_000277.1:c.168+5G>A, XM_011538422.1:c.168+5G>A, NM_001354304.1:c.168+5G>A, XM_017019370.2:c.168+5G>A, NM_000277.3:c.168+5G>A, ENST00000307000.7:c.153+5G>A, ENST00000546844.1:c.168+5G>A, ENST00000548677.2:n.255+5G>A, ENST00000548928.1:n.90+5G>A, ENST00000549111.5:n.264+5G>A, ENST00000550978.6:n.152+5G>A, ENST00000551337.5:c.168+5G>A, ENST00000551988.5:n.257+5G>A, ENST00000553106.5:c.168+5G>A, ENST00000635500.1:n.136+5G>A, NC_000012.12:g.102912786C>T, CM000674.2:g.102912786C>T, NC_000012.11:g.103306564C>T, CM000674.1:g.103306564C>T, NC_000012.10:g.101830694C>T, NG_008690.1:g.9817G>A, NG_008690.2:g.50625G>A, NM_000277.2(PAH):c.168+5G>A PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET] The c.168+5G>A variant has been identified in at least 4 probands with phenotypes ranging from mild HPA to classic PKU, with at least 2 probands excluding BH4 deficiency (PMIDs: 9429153, 26413448, 27121329). It has been detected in the homozygous form (PMID: 26413448) as well as in trans with pathogenic variants R297H (PMID: 9429153), I65T, and S349P (PMID: 27121329). This variant is absent from 1000G, ESP, and gnomAD databases. Computational analysis predicts an alteration of the WT donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3. 27121329, 26413448, 9429153, 27121329, 26413448, 9429153 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229453/MONDO:0009861/006 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103306564 102607 C A NM_000277.2(PAH):c.168+5G>T 102607 CA229455 NM_000277.2:c.168+5G>T, NC_000012.12:g.102912786C>A, CM000674.2:g.102912786C>A, NC_000012.11:g.103306564C>A, CM000674.1:g.103306564C>A, NC_000012.10:g.101830694C>A, NG_008690.1:g.9817G>T, NG_008690.2:g.50625G>T, NM_000277.1:c.168+5G>T, XM_011538422.1:c.168+5G>T, NM_001354304.1:c.168+5G>T, XM_017019370.2:c.168+5G>T, NM_000277.3:c.168+5G>T, ENST00000307000.7:c.153+5G>T, ENST00000546844.1:c.168+5G>T, ENST00000548677.2:n.255+5G>T, ENST00000548928.1:n.90+5G>T, ENST00000549111.5:n.264+5G>T, ENST00000550978.6:n.152+5G>T, ENST00000551337.5:c.168+5G>T, ENST00000551988.5:n.257+5G>T, ENST00000553106.5:c.168+5G>T, ENST00000635500.1:n.136+5G>T, NM_000277.2(PAH):c.168+5G>T PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PM3 [Unmet], PP3 [MET] The c.168+5G>T variant has been identified in at least 2 probands, with at least 1 classic PKU proband excluding BH4 deficiency (PMIDs: 30747360). This variant is absent from 1000G, ESP, and gnomAD databases. Computational analysis predicts an alteration of the WT donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as unknown significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3. 30747360 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229455/MONDO:0009861/006 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288689 102616 T C NM_000277.2(PAH):c.176A>G (p.Asp59Gly) 102616 CA229468 NM_000277.2:c.176A>G, NC_000012.12:g.102894911T>C, CM000674.2:g.102894911T>C, NC_000012.11:g.103288689T>C, CM000674.1:g.103288689T>C, NC_000012.10:g.101812819T>C, NG_008690.1:g.27692A>G, NG_008690.2:g.68500A>G, NM_000277.1:c.176A>G, XM_011538422.1:c.176A>G, NM_001354304.1:c.176A>G, XM_017019370.2:c.176A>G, NM_000277.3:c.176A>G, ENST00000307000.7:c.161A>G, ENST00000546844.1:c.176A>G, ENST00000548677.2:n.263A>G, ENST00000548928.1:n.98A>G, ENST00000549111.5:n.272A>G, ENST00000550978.6:n.160A>G, ENST00000551337.5:c.176A>G, ENST00000551988.5:n.265A>G, ENST00000553106.5:c.176A>G, ENST00000635500.1:n.144A>G, NM_000277.2(PAH):c.176A>G (p.Asp59Gly) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [Unmet], PP3 [Unmet] The c.176A>G (p.Asp59Gly) variant in PAH has not been reported in the literature to our knowledge. A reference from BioPKU/PAHdb is not located (Carducci C, 1999). It is absent from ExAC, gnomAD, 1000G, and ESP. There are conflicting predictions of pathogenicity: SIFT/Polyphen2: benign; MutationTaster: Damaging; REVEL=0.565. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229468/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103288678 102619 T G NM_000277.2(PAH):c.187A>C (p.Thr63Pro) 102619 CA229473 NM_000277.2:c.187A>C, NM_000277.1:c.187A>C, XM_011538422.1:c.187A>C, NM_001354304.1:c.187A>C, XM_017019370.2:c.187A>C, NM_000277.3:c.187A>C, ENST00000307000.7:c.172A>C, ENST00000546844.1:c.187A>C, ENST00000548677.2:n.274A>C, ENST00000548928.1:n.109A>C, ENST00000549111.5:n.283A>C, ENST00000550978.6:n.171A>C, ENST00000551337.5:c.187A>C, ENST00000551988.5:n.276A>C, ENST00000553106.5:c.187A>C, ENST00000635500.1:n.155A>C, NC_000012.12:g.102894900T>G, CM000674.2:g.102894900T>G, NC_000012.11:g.103288678T>G, CM000674.1:g.103288678T>G, NC_000012.10:g.101812808T>G, NG_008690.1:g.27703A>C, NG_008690.2:g.68511A>C, NM_000277.2(PAH):c.187A>C (p.Thr63Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [Unmet] The c.187A>C (p.Thr63Pro) variant in PAH was detected in 1 Danish PKU patient (Phenylalanine > 600 umol/L). Other causes of hyperphenylalaninemia had been ruled out. (PMID: 8406445). It was in cis with a p.H64N variant (No assertion provided, ClinVar). The c.187A>C variant is absent from ExAC, gnomAD, 1000G, and ESP. There are conflicting predictions of pathogenicity: SIFT:T,D; Polyphen2:D,P; MutationTaster:Disease causing; REVEL:0.768. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate. 8406445 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229473/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288675 102620 G T NM_000277.2(PAH):c.190C>A (p.His64Asn) 102620 CA229475 NM_000277.2:c.190C>A, NM_000277.1:c.190C>A, XM_011538422.1:c.190C>A, NM_001354304.1:c.190C>A, XM_017019370.2:c.190C>A, NM_000277.3:c.190C>A, ENST00000307000.7:c.175C>A, ENST00000546844.1:c.190C>A, ENST00000548677.2:n.277C>A, ENST00000548928.1:n.112C>A, ENST00000549111.5:n.286C>A, ENST00000550978.6:n.174C>A, ENST00000551337.5:c.190C>A, ENST00000551988.5:n.279C>A, ENST00000553106.5:c.190C>A, ENST00000635500.1:n.158C>A, NC_000012.12:g.102894897G>T, CM000674.2:g.102894897G>T, NC_000012.11:g.103288675G>T, CM000674.1:g.103288675G>T, NC_000012.10:g.101812805G>T, NG_008690.1:g.27706C>A, NG_008690.2:g.68514C>A, NM_000277.2(PAH):c.190C>A (p.His64Asn) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET] The c.190C>A (p.His64Asn) variant in PAH has been reported in a Danish mild PKU patient. Serum Phe levels exceeded 600 umol/L and other causes of hyperphenylalaninemia had been ruled out. It was In cis with p.T63P. PMID: 8406445. The c.190C>A variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, and MutationTaster. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. 8406445 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229475/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288671 102623 A T NM_000277.2(PAH):c.194T>A (p.Ile65Asn) 102623 CA229479 NM_000277.2:c.194T>A, NM_000277.1:c.194T>A, XM_011538422.1:c.194T>A, NM_001354304.1:c.194T>A, XM_017019370.2:c.194T>A, NM_000277.3:c.194T>A, ENST00000307000.7:c.179T>A, ENST00000546844.1:c.194T>A, ENST00000548677.2:n.281T>A, ENST00000548928.1:n.116T>A, ENST00000549111.5:n.290T>A, ENST00000550978.6:n.178T>A, ENST00000551337.5:c.194T>A, ENST00000551988.5:n.283T>A, ENST00000553106.5:c.194T>A, ENST00000635500.1:n.162T>A, NC_000012.12:g.102894893A>T, CM000674.2:g.102894893A>T, NC_000012.11:g.103288671A>T, CM000674.1:g.103288671A>T, NC_000012.10:g.101812801A>T, NG_008690.1:g.27710T>A, NG_008690.2:g.68518T>A, NM_000277.2(PAH):c.194T>A (p.Ile65Asn) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET] The c.194T>A (p.Ile65Asn) variant was identified in a patient with classic PKU. BH4 deficiency was ruled out. (PMID: 9521426). It was detected in trans with known pathogenic mutation c.143T>C (p.L48S). It has an extremely low frequency in PAGE (0.00026); and is absent from ExAC, 1000 Genomes, gnomAD. Multiple lines of computational evidence support a deleterious effect (SIFT, Polyphen-2, MutationTaster; REVEL=0.957). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PP3. 9521426, 9521426 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229479/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103310908 102626 T A NM_000277.2(PAH):c.1A>T (p.Met1Leu) 102626 CA229482 NM_000277.2:c.1A>T, NM_000277.1:c.1A>T, XM_011538422.1:c.1A>T, NM_001354304.1:c.1A>T, XM_017019370.2:c.1A>T, NM_000277.3:c.1A>T, ENST00000307000.7:c.-147A>T, ENST00000546844.1:c.1A>T, ENST00000547319.1:n.312A>T, ENST00000549111.5:n.97A>T, ENST00000551337.5:c.1A>T, ENST00000551988.5:n.90A>T, ENST00000553106.5:c.1A>T, ENST00000635500.1:n.29-4232A>T, NC_000012.12:g.102917130T>A, CM000674.2:g.102917130T>A, NC_000012.11:g.103310908T>A, CM000674.1:g.103310908T>A, NC_000012.10:g.101835038T>A, NG_008690.1:g.5473A>T, NG_008690.2:g.46281A>T, NM_000277.2(PAH):c.1A>T (p.Met1Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [MET], PM5 [Unmet], PP4 [MET] The PAH:p.M1L variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106); There are no other PAH RefSeq transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant was reported in trans with the pathogenic variant p.Arg241His (PM3) in 1 Mexican proband with mild PKU (PMID: 24941924; PP4). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PVS1. 24941924, 24941924 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229482/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103288654 102632 GAGA G NM_000277.1(PAH):c.208_210delTCT (p.Ser70del) 102632 CA229490 NM_000277.1:c.208_210delTCT, NM_000277.1:c.207_209delTTC, NM_000277.1:c.206_208delCTT, NM_000277.1:c.208_210del, XM_011538422.1:c.208_210del, NM_000277.2:c.208_210del, NM_001354304.1:c.208_210del, XM_017019370.2:c.208_210del, NM_000277.3:c.208_210del, ENST00000307000.7:c.193_195del, ENST00000546844.1:c.208_210del, ENST00000548677.2:n.295_297del, ENST00000548928.1:n.130_132del, ENST00000549111.5:n.304_306del, ENST00000550978.6:n.192_194del, ENST00000551337.5:c.208_210del, ENST00000551988.5:n.297_299del, ENST00000553106.5:c.208_210del, ENST00000635500.1:n.176_178del, NC_000012.12:g.102894879_102894881del, CM000674.2:g.102894879_102894881del, NC_000012.11:g.103288657_103288659del, CM000674.1:g.103288657_103288659del, NC_000012.10:g.101812787_101812789del, NG_008690.1:g.27724_27726del, NG_008690.2:g.68532_68534del, NM_000277.1(PAH):c.208_210delTCT (p.Ser70del) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PM3 [MET], PM4 [MET], PP4 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4, PM3, PS3, PM2, PM4). 25456745, 25456745 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-05 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229490/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103310907 102647 A C NM_000277.2(PAH):c.2T>G (p.Met1Arg) 102647 CA229509 NM_000277.2:c.2T>G, NC_000012.12:g.102917129A>C, CM000674.2:g.102917129A>C, NC_000012.11:g.103310907A>C, CM000674.1:g.103310907A>C, NC_000012.10:g.101835037A>C, NG_008690.1:g.5474T>G, NG_008690.2:g.46282T>G, NM_000277.1:c.2T>G, XM_011538422.1:c.2T>G, NM_001354304.1:c.2T>G, XM_017019370.2:c.2T>G, NM_000277.3:c.2T>G, ENST00000307000.7:c.-146T>G, ENST00000546844.1:c.2T>G, ENST00000547319.1:n.313T>G, ENST00000549111.5:n.98T>G, ENST00000551337.5:c.2T>G, ENST00000551988.5:n.91T>G, ENST00000553106.5:c.2T>G, ENST00000635500.1:n.29-4231T>G, NM_000277.2(PAH):c.2T>G (p.Met1Arg) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4-Moderate [MET], PM3 [MET], PM5 [Unmet], PP3 [Unmet] The PAH:p.M1R variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106). There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. The variant has been previously reported in 2 unrelated probands with classic PKU, in trans with the pathogenic variant p.R408W (PMID: 10679941; PM3); BH4 deficiency was excluded (PP4_Moderate). The variant is sufficiently rare in control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP4_moderate, PVS1. 10679941, 10679941 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229509/MONDO:0009861/006 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288554 102650 G T NM_000277.2(PAH):c.311C>A (p.Ala104Asp) 102650 CA229515 NM_000277.2:c.311C>A, NM_000277.1:c.311C>A, XM_011538422.1:c.311C>A, NM_001354304.1:c.311C>A, XM_017019370.2:c.311C>A, NM_000277.3:c.311C>A, ENST00000307000.7:c.296C>A, ENST00000546844.1:c.311C>A, ENST00000548928.1:n.233C>A, ENST00000549111.5:n.407C>A, ENST00000550978.6:n.295C>A, ENST00000551337.5:c.311C>A, ENST00000551988.5:n.400C>A, ENST00000553106.5:c.311C>A, NC_000012.12:g.102894776G>T, CM000674.2:g.102894776G>T, NC_000012.11:g.103288554G>T, CM000674.1:g.103288554G>T, NC_000012.10:g.101812684G>T, NG_008690.1:g.27827C>A, NG_008690.2:g.68635C>A, NM_000277.2(PAH):c.311C>A (p.Ala104Asp) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP3 [Unmet], PM3-Strong [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency: 0.00009 in gnomAD; PS3: 26% PAH enzyme activity; PM3_Strong: Detected with Y414C, pathogenic in ClinVar and V245L (P/LP) (PMID:9429153; PMID:24368688). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PS3, PM3_Strong). 9429153, 24368688 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-07 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229515/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103271313 102658 C A NM_000277.2(PAH):c.368G>T (p.Arg123Ile) 102658 CA286501 NM_000277.2:c.368G>T, NM_000277.1:c.368G>T, XM_011538422.1:c.368G>T, NM_001354304.1:c.368G>T, XM_017019370.2:c.368G>T, NM_000277.3:c.368G>T, ENST00000307000.7:c.353G>T, ENST00000549111.5:n.464G>T, ENST00000550978.6:n.352G>T, ENST00000551337.5:c.368G>T, ENST00000551988.5:n.457G>T, ENST00000553106.5:c.368G>T, NC_000012.12:g.102877535C>A, CM000674.2:g.102877535C>A, NC_000012.11:g.103271313C>A, CM000674.1:g.103271313C>A, NC_000012.10:g.101795443C>A, NG_008690.1:g.45068G>T, NG_008690.2:g.85876G>T, NM_000277.2(PAH):c.368G>T (p.Arg123Ile) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [Unmet], PP3 [MET] The c.368G>T (p.Arg123Ile) variant in PAH has not been reported in the literature to our knowledge. A reference listed in BioPKU/PAHdb cannot be located (Carducci, C 2009). This variant is absent from ExAC, gnomAD, 1000G, and ESP. Deleterious effect is predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.864. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA286501/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103271296 102660 C A NM_000277.2(PAH):c.385G>T (p.Asp129Tyr) 102660 CA286503 NM_000277.2:c.385G>T, NC_000012.12:g.102877518C>A, CM000674.2:g.102877518C>A, NC_000012.11:g.103271296C>A, CM000674.1:g.103271296C>A, NC_000012.10:g.101795426C>A, NG_008690.1:g.45085G>T, NG_008690.2:g.85893G>T, NM_000277.1:c.385G>T, XM_011538422.1:c.385G>T, NM_001354304.1:c.385G>T, XM_017019370.2:c.385G>T, NM_000277.3:c.385G>T, ENST00000307000.7:c.370G>T, ENST00000549111.5:n.481G>T, ENST00000550978.6:n.369G>T, ENST00000551337.5:c.385G>T, ENST00000551988.5:n.474G>T, ENST00000553106.5:c.385G>T, NM_000277.2(PAH):c.385G>T (p.Asp129Tyr) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [MET], PP3 [MET] The c.385G>T (p.Asp129Tyr) variant in PAH has not been reported in the literature to our knowledge. This variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). Multiple lines of computational evidence support a deleterious effect (PP3). There are 2 other missense variants at this residue in ClinVar; p.Asp129Gly is Likely Pathogenic by 1 submitter and PAH EP (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA286503/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103271295 102661 T C NM_000277.2(PAH):c.386A>G (p.Asp129Gly) 102661 CA229527 NM_000277.2:c.386A>G, NM_000277.1:c.386A>G, XM_011538422.1:c.386A>G, NM_001354304.1:c.386A>G, XM_017019370.2:c.386A>G, NM_000277.3:c.386A>G, ENST00000307000.7:c.371A>G, ENST00000549111.5:n.482A>G, ENST00000550978.6:n.370A>G, ENST00000551337.5:c.386A>G, ENST00000551988.5:n.475A>G, ENST00000553106.5:c.386A>G, NC_000012.12:g.102877517T>C, CM000674.2:g.102877517T>C, NC_000012.11:g.103271295T>C, CM000674.1:g.103271295T>C, NC_000012.10:g.101795425T>C, NG_008690.1:g.45086A>G, NG_008690.2:g.85894A>G, NM_000277.2(PAH):c.386A>G (p.Asp129Gly) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET] The c.386A>G (p.Asp129Gly) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8981952). This variant has extremely low frequency in gnomAD (MAF: 0.00001; PM2). This variant was detected in trans with known pathogenic variant c.1066-11G>A (PM3; PMID: 27121329). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. 8981952, 26666653, 23357515, 23062575, 27121329 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229527/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103271247 102667 T A NM_000277.2(PAH):c.434A>T (p.Asp145Val) 102667 CA229539 NM_000277.2:c.434A>T, NC_000012.12:g.102877469T>A, CM000674.2:g.102877469T>A, NC_000012.11:g.103271247T>A, CM000674.1:g.103271247T>A, NC_000012.10:g.101795377T>A, NG_008690.1:g.45134A>T, NG_008690.2:g.85942A>T, NM_000277.1:c.434A>T, XM_011538422.1:c.434A>T, NM_001354304.1:c.434A>T, XM_017019370.2:c.434A>T, NM_000277.3:c.434A>T, ENST00000307000.7:c.419A>T, ENST00000549111.5:n.530A>T, ENST00000550978.6:n.418A>T, ENST00000551988.5:n.523A>T, ENST00000553106.5:c.434A>T, NM_000277.2(PAH):c.434A>T (p.Asp145Val) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET], PM3-Strong [MET] The c.434A>T (p.Asp145Val) PAH variant has been identified in patients with PAH deficiency from the US, Germany, Italy and Spain. BH4 deficiency was excluded. (PMID: 8659548; 11385716; 12655553; 17096675; 23514811) It was detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653). It is found at extremely low frequency (MAF 0.00012 in gnomAD). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.987. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3 11385716, 12655553, 23514811, 8659548, 17096675, 8659548, 26666653, 24368688 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229539/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103271241 102670 G A NM_000277.2(PAH):c.440C>T (p.Pro147Leu) 102670 CA229543 NM_000277.2:c.440C>T, NC_000012.12:g.102877463G>A, CM000674.2:g.102877463G>A, NC_000012.11:g.103271241G>A, CM000674.1:g.103271241G>A, NC_000012.10:g.101795371G>A, NG_008690.1:g.45140C>T, NG_008690.2:g.85948C>T, NM_000277.1:c.440C>T, XM_011538422.1:c.440C>T, NM_001354304.1:c.440C>T, XM_017019370.2:c.440C>T, NM_000277.3:c.440C>T, ENST00000307000.7:c.425C>T, ENST00000549111.5:n.536C>T, ENST00000550978.6:n.424C>T, ENST00000551988.5:n.529C>T, ENST00000553106.5:c.440C>T, NM_000277.2(PAH):c.440C>T (p.Pro147Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET] The c.440C>T (p.Pro147Leu) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 27121329, 26322415, 16527067, 30050108, 28982351). This variant is absent in population databases (PM2). This variant was detected in trans with known pathogenic variants p.R261Ter (PMID: 27121329); c.611A>G (PMID: 30050108); p.S70del (PMID: 28982351) (PM3_strong). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. 26503515, 26322415, 28982351, 27121329, 26322415, 30050108 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229543/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260419 102686 C T NM_000277.2(PAH):c.464G>A (p.Arg155His) 102686 CA229559 NM_000277.2:c.464G>A, NC_000012.12:g.102866641C>T, CM000674.2:g.102866641C>T, NC_000012.11:g.103260419C>T, CM000674.1:g.103260419C>T, NC_000012.10:g.101784549C>T, NG_008690.1:g.55962G>A, NG_008690.2:g.96770G>A, NM_000277.1:c.464G>A, XM_011538422.1:c.464G>A, NM_001354304.1:c.464G>A, XM_017019370.2:c.464G>A, NM_000277.3:c.464G>A, ENST00000307000.7:c.449G>A, ENST00000549111.5:n.560G>A, ENST00000551988.5:n.530+10821G>A, ENST00000553106.5:c.464G>A, NM_000277.2(PAH):c.464G>A (p.Arg155His) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PP1 [MET], PS3 [Unmet], PM3-Strong [MET] The c.464G>A (p.Arg155His) has been reported in multiple individuals with mild hyperphenylalaninaemia, with BH4 deficiency excluded including 3 siblings (PP4_moderate, PMID: 9634518; PP1, PMID:18937047). This variant has low frequency in ExAC/gnomad (MAF=0.00012) in EA population (PM2). Multiple lines of computational evidence support a deleterious effect (PP3). This variant has been detected with 3 pathogenic variants: R243Q (PMID: 23932990), R111X (PMID: 24401910), IVS4+5G>T c.441+5G>T (PMID: 26210745) (PM3-strong). Experimental study showed the R155H mutant retained 55% activity, but this is higher than the cutoff set by PAH VCEP for PS3. (PMID: 18937047). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PP3, PP1. 9634518, 18937047, 18937047, 23932990, 26210745, 24401910, 18937047 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229559/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260419 102687 C G NM_000277.2(PAH):c.464G>C (p.Arg155Pro) 102687 CA229561 NM_000277.2:c.464G>C, NC_000012.12:g.102866641C>G, CM000674.2:g.102866641C>G, NC_000012.11:g.103260419C>G, CM000674.1:g.103260419C>G, NC_000012.10:g.101784549C>G, NG_008690.1:g.55962G>C, NG_008690.2:g.96770G>C, NM_000277.1:c.464G>C, XM_011538422.1:c.464G>C, NM_001354304.1:c.464G>C, XM_017019370.2:c.464G>C, NM_000277.3:c.464G>C, ENST00000307000.7:c.449G>C, ENST00000549111.5:n.560G>C, ENST00000551988.5:n.530+10821G>C, ENST00000553106.5:c.464G>C, NM_000277.2(PAH):c.464G>C (p.Arg155Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: absent from ExAC, gnomAD, 1000G, ESP. PAGE MAF=0.00066; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.967; PP4_Moderate: Detected in a patient with classic PKU. Cofactor deficiency excluded. (PMID:10679941); PM3: Detected in trans with R408W (P) (PMID:10679941). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3). 10679941, 10679941 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229561/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103310863 102689 A G NM_000277.2(PAH):c.46T>C (p.Ser16Pro) 102689 CA229564 NM_000277.2:c.46T>C, NM_000277.1:c.46T>C, XM_011538422.1:c.46T>C, NM_001354304.1:c.46T>C, XM_017019370.2:c.46T>C, NM_000277.3:c.46T>C, ENST00000307000.7:c.-102T>C, ENST00000546844.1:c.46T>C, ENST00000547319.1:n.357T>C, ENST00000549111.5:n.142T>C, ENST00000550978.6:n.30T>C, ENST00000551337.5:c.46T>C, ENST00000551988.5:n.135T>C, ENST00000553106.5:c.46T>C, ENST00000635500.1:n.29-4187T>C, NC_000012.12:g.102917085A>G, CM000674.2:g.102917085A>G, NC_000012.11:g.103310863A>G, CM000674.1:g.103310863A>G, NC_000012.10:g.101834993A>G, NG_008690.1:g.5518T>C, NG_008690.2:g.46326T>C, NM_000277.2(PAH):c.46T>C (p.Ser16Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], BP4 [MET] VUS: The c.46T>C (p.S16P) variant in PAH has not been reported in the medical literature. It is tolerated by computation predictors: SIFT, Polyphen, MutationTaster, and REVEL=0.567 (BP4). It is however absent from population databases, including gnomAD, 1000 Genomes, and ESP (PM2). In summary this variant meets the criteria to be classified as uncertain significance. PAH-specific ACMG/AMP criteria applied: BP4, PM2. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229564/MONDO:0009861/006 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260411 102693 G A NM_000277.2(PAH):c.472C>T (p.Arg158Trp) 102693 CA229570 NM_000277.2:c.472C>T, NC_000012.12:g.102866633G>A, CM000674.2:g.102866633G>A, NC_000012.11:g.103260411G>A, CM000674.1:g.103260411G>A, NC_000012.10:g.101784541G>A, NG_008690.1:g.55970C>T, NG_008690.2:g.96778C>T, NM_000277.1:c.472C>T, XM_011538422.1:c.472C>T, NM_001354304.1:c.472C>T, XM_017019370.2:c.472C>T, NM_000277.3:c.472C>T, ENST00000307000.7:c.457C>T, ENST00000549111.5:n.568C>T, ENST00000551988.5:n.530+10829C>T, ENST00000553106.5:c.472C>T, NM_000277.2(PAH):c.472C>T (p.Arg158Trp) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong). 9634518, 10429004, 1307609, 23430918, 14681498 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229570/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260410 102694 C G NM_000277.2(PAH):c.473G>C (p.Arg158Pro) 102694 CA229571 NM_000277.2:c.473G>C, NM_000277.1:c.473G>C, XM_011538422.1:c.473G>C, NM_001354304.1:c.473G>C, XM_017019370.2:c.473G>C, NM_000277.3:c.473G>C, ENST00000307000.7:c.458G>C, ENST00000549111.5:n.569G>C, ENST00000551988.5:n.530+10830G>C, ENST00000553106.5:c.473G>C, NC_000012.12:g.102866632C>G, CM000674.2:g.102866632C>G, NC_000012.11:g.103260410C>G, CM000674.1:g.103260410C>G, NC_000012.10:g.101784540C>G, NG_008690.1:g.55971G>C, NG_008690.2:g.96779G>C, NM_000277.2(PAH):c.473G>C (p.Arg158Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM5 [MET], PM3 [MET], PP3 [MET], PP4 [MET] The c.473G>C (p.Arg158Pro) variant in PAH was reported in a patient with Mild Hyperphenylalaninemia (Phenylalanine level 380 umol/l) PMID: 8659548. It was detected with V388M (known pathogenic variant). It has an extremely low frequency in ExAC and gnomAD (MAF 0.00002). It is predicted deleterious in SIFT, Polyphen2, MutationTaster and REVEL=0.98. Two different pathogenic missense changes at this amino acid have been seen before (R158W, R158Q). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PM5, PP3, PP4. 8659548, 8659548 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229571/MONDO:0009861/006 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103310860 102696 CAG C NM_000277.2(PAH):c.47_48delCT (p.Ser16Terfs) 102696 CA229574 NM_000277.2:c.47_48delCT, NC_000012.12:g.102917087_102917088del, CM000674.2:g.102917087_102917088del, NC_000012.11:g.103310865_103310866del, CM000674.1:g.103310865_103310866del, NC_000012.10:g.101834995_101834996del, NG_008690.1:g.5519_5520del, NG_008690.2:g.46327_46328del, NM_000277.1:c.47_48del, XM_011538422.1:c.47_48del, NM_000277.2:c.47_48del, NM_001354304.1:c.47_48del, XM_017019370.2:c.47_48del, NM_000277.3:c.47_48del, ENST00000307000.7:c.-101_-100del, ENST00000546844.1:c.47_48del, ENST00000547319.1:n.358_359del, ENST00000549111.5:n.143_144del, ENST00000550978.6:n.31_32del, ENST00000551337.5:c.47_48del, ENST00000551988.5:n.136_137del, ENST00000553106.5:c.47_48del, ENST00000635500.1:n.29-4186_29-4185del, NM_000277.2(PAH):c.47_48delCT (p.Ser16Terfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [MET], PP3 [Unmet], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PM2: ExAC:8.238e-06; gnomAD:0.000004062; 1000G + ESP: absent; PVS1: Null variant- frameshift. Subject to nonsense mediated decay.; PM3: found in trans with L48S (VarID608, Pathogenic) (PMID:8535445); PP4: 47delCT found in 1 patient with moderate PKU. BH4 deficiency not ruled out. (PMID:8535445). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PM3, PP4). 8535445, 8535445 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229574/MONDO:0009861/006 0.9971 Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260393 102698 T C NM_000277.2(PAH):c.490A>G (p.Ile164Val) 102698 CA229576 NM_000277.2:c.490A>G, NM_000277.1:c.490A>G, XM_011538422.1:c.490A>G, NM_001354304.1:c.490A>G, XM_017019370.2:c.490A>G, NM_000277.3:c.490A>G, ENST00000307000.7:c.475A>G, ENST00000549111.5:n.586A>G, ENST00000551988.5:n.530+10847A>G, ENST00000553106.5:c.490A>G, NC_000012.12:g.102866615T>C, CM000674.2:g.102866615T>C, NC_000012.11:g.103260393T>C, CM000674.1:g.103260393T>C, NC_000012.10:g.101784523T>C, NG_008690.1:g.55988A>G, NG_008690.2:g.96796A>G, NM_000277.2(PAH):c.490A>G (p.Ile164Val) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [Unmet], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM2: ExAC MAF: 0.00012; PP4_Moderate: Detected in patients with PKU/HPA. BH4 deficiency excluded. (PMID:11244681; PMID:23942198); PM3_Strong: Detected with D145V, A403V (Pathogenic) (PMID:11244681; PMID:23942198). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). 11244681, 23942198, 11244681, 23942198 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-13 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229576/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103260390 102700 C T NM_000277.2(PAH):c.493G>A (p.Ala165Thr) 102700 CA229579 NM_000277.2:c.493G>A, NM_000277.1:c.493G>A, XM_011538422.1:c.493G>A, NM_001354304.1:c.493G>A, XM_017019370.2:c.493G>A, NM_000277.3:c.493G>A, ENST00000307000.7:c.478G>A, ENST00000549111.5:n.589G>A, ENST00000551988.5:n.530+10850G>A, ENST00000553106.5:c.493G>A, NC_000012.12:g.102866612C>T, CM000674.2:g.102866612C>T, NC_000012.11:g.103260390C>T, CM000674.1:g.103260390C>T, NC_000012.10:g.101784520C>T, NG_008690.1:g.55991G>A, NG_008690.2:g.96799G>A, NM_000277.2(PAH):c.493G>A (p.Ala165Thr) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET], PP1 [MET] The c.493G>A (p.Ala165Thr) variant in PAH has been reported in multiple individuals with PKU, including siblings (BH4 deficiency excluded). (PP4_Moderate, PMID: 8981952; PP1, PMID: 26666653). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with c.1066-11G>A (PM3; PMID: 10598814). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP1, PP3. 8981952, 19786003, 10598814, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229579/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260390 102701 C G NM_000277.2(PAH):c.493G>C (p.Ala165Pro) 102701 CA229581 NM_000277.2:c.493G>C, NC_000012.12:g.102866612C>G, CM000674.2:g.102866612C>G, NC_000012.11:g.103260390C>G, CM000674.1:g.103260390C>G, NC_000012.10:g.101784520C>G, NG_008690.1:g.55991G>C, NG_008690.2:g.96799G>C, NM_000277.1:c.493G>C, XM_011538422.1:c.493G>C, NM_001354304.1:c.493G>C, XM_017019370.2:c.493G>C, NM_000277.3:c.493G>C, ENST00000307000.7:c.478G>C, ENST00000549111.5:n.589G>C, ENST00000551988.5:n.530+10850G>C, ENST00000553106.5:c.493G>C, NM_000277.2(PAH):c.493G>C (p.Ala165Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM3 [Unmet], PP3 [MET], PP4 [MET] The c.493G>C (p.Ala165Pro) variant in PAH has been reported in a French patient with mild PKU with p.Glu390Gly, but parents were not tested (PP4; PMID: 26666653) This variant is absent from 1000G and ESP, and has extremely low frequency in ExAC/gnomAD: MAF 0.00001 (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.956 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. 26666653, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229581/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103260385 102702 G T NM_000277.2(PAH):c.498C>A (p.Tyr166Ter) 102702 CA229583 NM_000277.2:c.498C>A, NM_000277.1:c.498C>A, XM_011538422.1:c.498C>A, NM_001354304.1:c.498C>A, XM_017019370.2:c.498C>A, NM_000277.3:c.498C>A, ENST00000307000.7:c.483C>A, ENST00000549111.5:n.594C>A, ENST00000551988.5:n.530+10855C>A, ENST00000553106.5:c.498C>A, NC_000012.12:g.102866607G>T, CM000674.2:g.102866607G>T, NC_000012.11:g.103260385G>T, CM000674.1:g.103260385G>T, NC_000012.10:g.101784515G>T, NG_008690.1:g.55996C>A, NG_008690.2:g.96804C>A, NM_000277.2(PAH):c.498C>A (p.Tyr166Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [MET], PP4 [MET] The c.498C>A (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in individuals with Classic PKU in German and Chinese cohorts. (PP4, PMID:16256386; 10394930). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). This variant was detected with multiple known pathogenic variants (PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. 16256386, 16256386 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229583/MONDO:0009861/006 0.9941 Likely Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260383 102703 T C NM_000277.2(PAH):c.500A>G (p.Asn167Ser) 102703 CA229585 NM_000277.2:c.500A>G, NC_000012.12:g.102866605T>C, CM000674.2:g.102866605T>C, NC_000012.11:g.103260383T>C, CM000674.1:g.103260383T>C, NC_000012.10:g.101784513T>C, NG_008690.1:g.55998A>G, NG_008690.2:g.96806A>G, NM_000277.1:c.500A>G, XM_011538422.1:c.500A>G, NM_001354304.1:c.500A>G, XM_017019370.2:c.500A>G, NM_000277.3:c.500A>G, ENST00000307000.7:c.485A>G, ENST00000549111.5:n.596A>G, ENST00000551988.5:n.530+10857A>G, ENST00000553106.5:c.500A>G, NM_000277.2(PAH):c.500A>G (p.Asn167Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance BS1 [MET], PP4 [MET], PP3 [Unmet] PAH-specific ACMG/AMP criteria applied: PP4: N167S was observed in 1 case (genotype N167S/-) with benign persistent hyperphenylalaninemia (200-600 uM). (PMID:11385716); BS1: gnomAD MAF: 0.01461. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4, BS1). 11385716 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-13 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229585/MONDO:0009861/006 0.1 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103260379 102705 GT G NM_000277.2(PAH):c.503delA (p.Tyr168Serfs) 102705 CA229588 NM_000277.2:c.503delA, NC_000012.12:g.102866602del, CM000674.2:g.102866602del, NC_000012.11:g.103260380del, CM000674.1:g.103260380del, NC_000012.10:g.101784510del, NG_008690.1:g.56001del, NG_008690.2:g.96809del, NM_000277.1:c.503del, XM_011538422.1:c.503del, NM_000277.2:c.503del, NM_001354304.1:c.503del, XM_017019370.2:c.503del, NM_000277.3:c.503del, ENST00000307000.7:c.488del, ENST00000549111.5:n.599del, ENST00000551988.5:n.530+10860del, ENST00000553106.5:c.503del, NM_000277.2(PAH):c.503delA (p.Tyr168Serfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. ExAC MAF: 0.00001.; PP4: Detected in PKU patient in international phase II clinical trial for sapropterin. (PMID:23430918). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4). 23430918 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229588/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260377 102706 C T NM_000277.2(PAH):c.506G>A (p.Arg169His) 102706 CA286505 NM_000277.2:c.506G>A, NC_000012.12:g.102866599C>T, CM000674.2:g.102866599C>T, NC_000012.11:g.103260377C>T, CM000674.1:g.103260377C>T, NC_000012.10:g.101784507C>T, NG_008690.1:g.56004G>A, NG_008690.2:g.96812G>A, NM_000277.1:c.506G>A, XM_011538422.1:c.506G>A, NM_001354304.1:c.506G>A, XM_017019370.2:c.506G>A, NM_000277.3:c.506G>A, ENST00000307000.7:c.491G>A, ENST00000549111.5:n.602G>A, ENST00000551988.5:n.530+10863G>A, ENST00000553106.5:c.506G>A, NM_000277.2(PAH):c.506G>A (p.Arg169His) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [Unmet], PP4-Moderate [MET], PP3 [Unmet], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PP4_Moderate: This variant has been reported in multiple mild hyperphenylalaninaemia (MHP) patients, with BH4 defects excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:10234516); PM3_Strong: Detected with P281L and A403V, both pathogenic variants (PMID:10234516). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_Strong). 10234516, 10234516 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA286505/MONDO:0009861/006 0.3246 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249109 102716 C T NM_000277.2(PAH):c.511G>A (p.Gly171Arg) 102716 CA229598 NM_000277.2:c.511G>A, NC_000012.12:g.102855331C>T, CM000674.2:g.102855331C>T, NC_000012.11:g.103249109C>T, CM000674.1:g.103249109C>T, NC_000012.10:g.101773239C>T, NG_008690.1:g.67272G>A, NG_008690.2:g.108080G>A, NM_000277.1:c.511G>A, XM_011538422.1:c.511G>A, NM_001354304.1:c.511G>A, XM_017019370.2:c.511G>A, NM_000277.3:c.511G>A, ENST00000307000.7:c.496G>A, ENST00000549111.5:n.607G>A, ENST00000551988.5:n.532G>A, ENST00000553106.5:c.511G>A, NM_000277.2(PAH):c.511G>A (p.Gly171Arg) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.966; PP4_Moderate: Detected in PKU patients. BH4 deficiency assessed. Upgraded per ClinGen PAH EP. (PMID:26600521; PMID:23430918); PM3_Strong: Detected with c.611A>G (P/LP) and R408W (P). Upgraded per ClinGen SVI workgroup. (PMID:23430918; PMID:26600521). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong). 23430918, 26600521, 23430918, 26600521 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229598/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249100 102720 T C NM_000277.1(PAH):c.520A>G (p.Ile174Val) 102720 CA229603 NM_000277.1:c.520A>G, XM_011538422.1:c.520A>G, NM_000277.2:c.520A>G, NM_001354304.1:c.520A>G, XM_017019370.2:c.520A>G, NM_000277.3:c.520A>G, ENST00000307000.7:c.505A>G, ENST00000549111.5:n.616A>G, ENST00000551988.5:n.541A>G, ENST00000553106.5:c.520A>G, NC_000012.12:g.102855322T>C, CM000674.2:g.102855322T>C, NC_000012.11:g.103249100T>C, CM000674.1:g.103249100T>C, NC_000012.10:g.101773230T>C, NG_008690.1:g.67281A>G, NG_008690.2:g.108089A>G, NM_000277.1(PAH):c.520A>G (p.Ile174Val) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM5 [Unmet], PM3 [MET], PP3 [MET], PP4 [MET] "PAH-specific ACMG/AMP criteria applied: PM2: Not found in any population databases; PP3: All predictors agree--damaging; PM3: Single patient IVS4+5G>T (null) / I174V (Bercovich 2008 PMID 18299955) (PMID:18299955); PP4: Two independent patients (one in Zschocke (PMID 10394930) and one in Bercovich (PMID 18299955) with ""PKU"". While no specific levels are mentioned, they are followed in clinic and were diagnosed with Phe >120umol/L. BH4 defect WAS NOT excluded in either paper.. In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM3, PP4)." 18299955 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229603/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103249099 102721 A G NM_000277.2(PAH):c.521T>C (p.Ile174Thr) 102721 CA229604 NM_000277.2:c.521T>C, NM_000277.1:c.521T>C, XM_011538422.1:c.521T>C, NM_001354304.1:c.521T>C, XM_017019370.2:c.521T>C, NM_000277.3:c.521T>C, ENST00000307000.7:c.506T>C, ENST00000549111.5:n.617T>C, ENST00000551988.5:n.542T>C, ENST00000553106.5:c.521T>C, NC_000012.12:g.102855321A>G, CM000674.2:g.102855321A>G, NC_000012.11:g.103249099A>G, CM000674.1:g.103249099A>G, NC_000012.10:g.101773229A>G, NG_008690.1:g.67282T>C, NG_008690.2:g.108090T>C, NM_000277.2(PAH):c.521T>C (p.Ile174Thr) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET], PS3 [MET] The c.521T>C (p.Ile174Thr) variant in PAH has been reported in 2 individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 9634518). This variant is absent from ExAC/gnomAD, 1000 Genomes, ESP (PM2). This variant has 1-15% enzyme activity (PS3; PMID: 11161839). This variant was detected in with p.F299C (P/LP, 6 submitters) (PM3; PMID: 23842451). Computational prediction tools and conservation analysis suggest that the variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PP3 9634518, 23842451, 11161839 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229604/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249094 102723 G A NM_000277.2(PAH):c.526C>T (p.Arg176Ter) 102723 CA275338 NM_000277.2:c.526C>T, NC_000012.12:g.102855316G>A, CM000674.2:g.102855316G>A, NC_000012.11:g.103249094G>A, CM000674.1:g.103249094G>A, NC_000012.10:g.101773224G>A, NG_008690.1:g.67287C>T, NG_008690.2:g.108095C>T, NM_000277.1:c.526C>T, XM_011538422.1:c.526C>T, NM_001354304.1:c.526C>T, XM_017019370.2:c.526C>T, NM_000277.3:c.526C>T, ENST00000307000.7:c.511C>T, ENST00000549111.5:n.622C>T, ENST00000551988.5:n.547C>T, ENST00000553106.5:c.526C>T, NM_000277.2(PAH):c.526C>T (p.Arg176Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PVS1 [MET], PM2 [MET], PP4-Moderate [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: ExAC MAF: 0.00010; PP4_Moderate: BH4 defect excluded in all patients in Liu 2015. Identified in 6 patients in this study (PMID:10394930; PMID:26600521); PM3_Strong: Identified in 6 patients, in trans with R243Q and R241C (both pathogenic) (PMID:26600521). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate, PM3_Strong). 26600521, 10394930, 26600521 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-13 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA275338/MONDO:0009861/006 0.9941 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249091 102726 C T NM_000277.2(PAH):c.529G>A (p.Val177Met) 102726 CA229609 NM_000277.2:c.529G>A, NC_000012.12:g.102855313C>T, CM000674.2:g.102855313C>T, NC_000012.11:g.103249091C>T, CM000674.1:g.103249091C>T, NC_000012.10:g.101773221C>T, NG_008690.1:g.67290G>A, NG_008690.2:g.108098G>A, NM_000277.1:c.529G>A, XM_011538422.1:c.529G>A, NM_001354304.1:c.529G>A, XM_017019370.2:c.529G>A, NM_000277.3:c.529G>A, ENST00000307000.7:c.514G>A, ENST00000549111.5:n.625G>A, ENST00000551988.5:n.550G>A, ENST00000553106.5:c.529G>A, NM_000277.2(PAH):c.529G>A (p.Val177Met) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [MET], PP3 [MET], PM3-Strong [MET] The c.529G>A (p.Val177Met) variant in PAH was detected in a patient with Mild hyperphenylalaninemia (BH4 deficiency ruled out). PMID: 12501224 It has been detected with known pathogenic variants R408W (PMID: 12501224), and IVS12+1G>A (PMID: 23764561). It is absent from 1000G, ESP, and gnomAD; and at extremely low frequency in ExAC (MAF=0.00003). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.89. A different pathogenic missense change has been seen at this amino acid (V177L). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3. 12501224, 23764561, 12501224 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229609/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103249085 102729 A T NM_000277.2(PAH):c.535T>A (p.Tyr179Asn) 102729 CA229613 NM_000277.2:c.535T>A, NC_000012.12:g.102855307A>T, CM000674.2:g.102855307A>T, NC_000012.11:g.103249085A>T, CM000674.1:g.103249085A>T, NC_000012.10:g.101773215A>T, NG_008690.1:g.67296T>A, NG_008690.2:g.108104T>A, NM_000277.1:c.535T>A, XM_011538422.1:c.535T>A, NM_001354304.1:c.535T>A, XM_017019370.2:c.535T>A, NM_000277.3:c.535T>A, ENST00000307000.7:c.520T>A, ENST00000549111.5:n.631T>A, ENST00000551988.5:n.556T>A, ENST00000553106.5:c.535T>A, NM_000277.2(PAH):c.535T>A (p.Tyr179Asn) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.929; PP4_Moderate: Detected in 1 PKU patient, primary BH4 deficiency excluded. Upgraded per ClinGen PAH EP. (PMID:23430918); PM3: Detected with c.1066-11G>A (P) (PMID:23430918). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3). 23430918, 23430918 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229613/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249061 102735 A G NM_000277.2(PAH):c.559T>C (p.Trp187Arg) 102735 CA229622 NM_000277.2:c.559T>C, NM_000277.1:c.559T>C, XM_011538422.1:c.559T>C, NM_001354304.1:c.559T>C, XM_017019370.2:c.559T>C, NM_000277.3:c.559T>C, ENST00000307000.7:c.544T>C, ENST00000549111.5:n.655T>C, ENST00000551988.5:n.580T>C, ENST00000553106.5:c.559T>C, NC_000012.12:g.102855283A>G, CM000674.2:g.102855283A>G, NC_000012.11:g.103249061A>G, CM000674.1:g.103249061A>G, NC_000012.10:g.101773191A>G, NG_008690.1:g.67320T>C, NG_008690.2:g.108128T>C, NM_000277.2(PAH):c.559T>C (p.Trp187Arg) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], BS1 [Unmet], PP3 [MET], BP4 [Unmet], BA1 [Unmet], PM3-Strong [MET] The PAH: c.559T>C (p.Trp187Arg) variant was found in two cases in trans with other P/LP alleles: one case with classic PKU (assessed via plasma Phe measurement in trans with the p.R158Q allele (PMID: 18956252) and one case whose PKU sub-phenotype was not mentioned in trans with the p.R261Q allele (PMID: 23074961) (PM3_Strong). It has also been found in trans with the p.Gln419Arg allele, classified as Likely Pathogenic in ClinVar, in 1 case with mild hyperphenylalanemia (BH4 deficiency excluded. PP4_moderate. PMID: 28982351). The variant is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is predicted damaging by multiple lines of computational evidence: SIFT, Polyphen2, Mutation Taster, REVEL = 0.918 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. 18956252, 28982351, 18956252, 28982351, 23074961 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229622/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249059 102736 C T NM_000277.2(PAH):c.561G>A (p.Trp187Ter) 102736 CA229624 NM_000277.2:c.561G>A, NC_000012.12:g.102855281C>T, CM000674.2:g.102855281C>T, NC_000012.11:g.103249059C>T, CM000674.1:g.103249059C>T, NC_000012.10:g.101773189C>T, NG_008690.1:g.67322G>A, NG_008690.2:g.108130G>A, NM_000277.1:c.561G>A, XM_011538422.1:c.561G>A, NM_001354304.1:c.561G>A, XM_017019370.2:c.561G>A, NM_000277.3:c.561G>A, ENST00000307000.7:c.546G>A, ENST00000549111.5:n.657G>A, ENST00000551988.5:n.582G>A, ENST00000553106.5:c.561G>A, NM_000277.2(PAH):c.561G>A (p.Trp187Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PVS1 [MET], PM2 [MET], PP4-Moderate [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: Extremely low frequency in gnomAD. MAF=0.00002.; PP4_Moderate: Detected in 3 chromosomes of patients with PAH deficiency. BH4 deficiency ruled out. (PMID:8268925). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate). 8268925 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229624/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249039 102742 A G NM_000277.2(PAH):c.581T>C (p.Leu194Pro) 102742 CA229633 NM_000277.2:c.581T>C, NM_000277.1:c.581T>C, XM_011538422.1:c.581T>C, NM_001354304.1:c.581T>C, XM_017019370.2:c.581T>C, NM_000277.3:c.581T>C, ENST00000307000.7:c.566T>C, ENST00000549111.5:n.677T>C, ENST00000553106.5:c.581T>C, NC_000012.12:g.102855261A>G, CM000674.2:g.102855261A>G, NC_000012.11:g.103249039A>G, CM000674.1:g.103249039A>G, NC_000012.10:g.101773169A>G, NG_008690.1:g.67342T>C, NG_008690.2:g.108150T>C, NM_000277.2(PAH):c.581T>C (p.Leu194Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. gnomAD MAF:0.00004.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.899; PM3_Strong: Detected in trans with V245A and R261X, both pathogenic (PMID:7981714; PMID:16601866); PP4_Moderate: Detected in 3 patients (1 HPA, 1 PKU). BH4 deficiency excluded in 2 patients. (PMID:8533759; PMID:7981714; PMID:9012412; PMID:16601866). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM3_Strong, PP4_Moderate). 16601866, 9012412, 8533759, 7981714, 16601866, 7981714 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-13 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229633/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103310851 102744 G A NM_000277.2(PAH):c.58C>T (p.Gln20Ter) 102744 CA229635 NM_000277.2:c.58C>T, NM_000277.1:c.58C>T, XM_011538422.1:c.58C>T, NM_001354304.1:c.58C>T, XM_017019370.2:c.58C>T, NM_000277.3:c.58C>T, ENST00000307000.7:c.-90C>T, ENST00000546844.1:c.58C>T, ENST00000547319.1:n.369C>T, ENST00000549111.5:n.154C>T, ENST00000550978.6:n.42C>T, ENST00000551337.5:c.58C>T, ENST00000551988.5:n.147C>T, ENST00000553106.5:c.58C>T, ENST00000635500.1:n.29-4175C>T, NC_000012.12:g.102917073G>A, CM000674.2:g.102917073G>A, NC_000012.11:g.103310851G>A, CM000674.1:g.103310851G>A, NC_000012.10:g.101834981G>A, NG_008690.1:g.5530C>T, NG_008690.2:g.46338C>T, NM_000277.2(PAH):c.58C>T (p.Gln20Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] Pathogenic: The c.58C>T (p.Gln20Ter) is a null variant reported in one patient with classic PKU phenotype (PVS1, PP4, PMID: 9391881). This variant is absent from population databases, including gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. 9391881 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229635/MONDO:0009861/006 0.9971 Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103310850 102749 T A NM_000277.2(PAH):c.59A>T (p.Gln20Leu) 102749 CA229641 NM_000277.2:c.59A>T, NC_000012.12:g.102917072T>A, CM000674.2:g.102917072T>A, NC_000012.11:g.103310850T>A, CM000674.1:g.103310850T>A, NC_000012.10:g.101834980T>A, NG_008690.1:g.5531A>T, NG_008690.2:g.46339A>T, NM_000277.1:c.59A>T, XM_011538422.1:c.59A>T, NM_001354304.1:c.59A>T, XM_017019370.2:c.59A>T, NM_000277.3:c.59A>T, ENST00000307000.7:c.-89A>T, ENST00000546844.1:c.59A>T, ENST00000547319.1:n.370A>T, ENST00000549111.5:n.155A>T, ENST00000550978.6:n.43A>T, ENST00000551337.5:c.59A>T, ENST00000551988.5:n.148A>T, ENST00000553106.5:c.59A>T, ENST00000635500.1:n.29-4174A>T, NM_000277.2(PAH):c.59A>T (p.Gln20Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP3 [Unmet], PP4 [MET], PM3-Supporting [MET] VUS:The c.59A>T (p.Q20L) variant was detected in trans with a known pathogenic variant (c.1315+1G>A) in a patient with hyperphenylalaninemia (parental testing not reported) (PP4, PM3-supporting; PMID: 10679941). This variant is absent from population databases including, gnomAD, ESP, and 1000 Genomes (PM2). Computation predictors on protein structure and function indicate conflicting results (SIFT: tolerated, Polyphen: Benign, MutationTaster: Disease causing, REVEL=0.582). In summary this variant meets the criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3-supporting, PP4. 10679941, 10679941 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229641/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103310849 102757 C G NM_000277.2(PAH):c.60G>C (p.Gln20His) 102757 CA229651 NM_000277.2:c.60G>C, NM_000277.1:c.60G>C, XM_011538422.1:c.60G>C, NM_001354304.1:c.60G>C, XM_017019370.2:c.60G>C, NM_000277.3:c.60G>C, ENST00000307000.7:c.-88G>C, ENST00000546844.1:c.60G>C, ENST00000547319.1:n.371G>C, ENST00000549111.5:n.156G>C, ENST00000550978.6:n.44G>C, ENST00000551337.5:c.60G>C, ENST00000551988.5:n.149G>C, ENST00000553106.5:c.60G>C, ENST00000635500.1:n.29-4173G>C, NC_000012.12:g.102917071C>G, CM000674.2:g.102917071C>G, NC_000012.11:g.103310849C>G, CM000674.1:g.103310849C>G, NC_000012.10:g.101834979C>G, NG_008690.1:g.5532G>C, NG_008690.2:g.46340G>C, NM_000277.2(PAH):c.60G>C (p.Gln20His) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM3 [Unmet], PP3 [MET], PP4 [MET] The c.60G>C (p.Q20H) variant has been reported in 1 patient with PKU (not excluding BH4 deficiency), who carried 2 pathogenic variants (p.R158Q, p.R408W) in PAH (PMID: 18321666, PMID: 23430918). This variant is absent from population databases, including 1000 Genomes, ESP, and gnomAD. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.571. In summary, this variant meets our criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PP4. 23430918, 18321666, 18321666 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229651/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103248987 102767 TG T NM_000277.2(PAH):c.632delC (p.Pro211Hisfs) 102767 CA229667 NM_000277.2:c.632delC, NC_000012.12:g.102855211del, CM000674.2:g.102855211del, NC_000012.11:g.103248989del, CM000674.1:g.103248989del, NC_000012.10:g.101773119del, NG_008690.1:g.67393del, NG_008690.2:g.108201del, NM_000277.1:c.632del, XM_011538422.1:c.632del, NM_000277.2:c.632del, NM_001354304.1:c.632del, XM_017019370.2:c.632del, NM_000277.3:c.632del, ENST00000307000.7:c.617del, ENST00000549111.5:n.728del, ENST00000553106.5:c.632del, NM_000277.2(PAH):c.632delC (p.Pro211Hisfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [MET], PP4 [MET] The c.632delC (p.Pro211Hisfs) variant in PAH leads to a frameshift at amino acid 211/432. It is identified with low frequency in population databases (1.648e-5). It has been identified in two individuals with Phenylketonuria as a homozygous variant and in trans with c.1066-11G>A (PMID: 26413448; 26666653). It has been described in multiple patients with PKU, although a defect in BH4 metabolism has not been excluded as a cause of elevated phenylalanine in any case. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. 26413448, 26666653, 26413448, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229667/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103248970 102772 C T NM_000277.2(PAH):c.650G>A (p.Cys217Tyr) 102772 CA229674 NM_000277.2:c.650G>A, NC_000012.12:g.102855192C>T, CM000674.2:g.102855192C>T, NC_000012.11:g.103248970C>T, CM000674.1:g.103248970C>T, NC_000012.10:g.101773100C>T, NG_008690.1:g.67411G>A, NG_008690.2:g.108219G>A, NM_000277.1:c.650G>A, XM_011538422.1:c.650G>A, NM_001354304.1:c.650G>A, XM_017019370.2:c.650G>A, NM_000277.3:c.650G>A, ENST00000307000.7:c.635G>A, ENST00000549111.5:n.746G>A, ENST00000553106.5:c.650G>A, NM_000277.2(PAH):c.650G>A (p.Cys217Tyr) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET] The c.650G>A (p.Cys217Tyr) variant in PAH was reported in 1 Japanese PKU patient. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. (PMID: 21307867). This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.982. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3. 21307867 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229674/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103248932 102784 C T NM_000277.1(PAH):c.688G>A (p.Val230Ile) 102784 CA286506 NM_000277.1:c.688G>A, NC_000012.12:g.102855154C>T, CM000674.2:g.102855154C>T, NC_000012.11:g.103248932C>T, CM000674.1:g.103248932C>T, NC_000012.10:g.101773062C>T, NG_008690.1:g.67449G>A, NG_008690.2:g.108257G>A, XM_011538422.1:c.688G>A, NM_000277.2:c.688G>A, NM_001354304.1:c.688G>A, XM_017019370.2:c.688G>A, NM_000277.3:c.688G>A, ENST00000307000.7:c.673G>A, ENST00000549111.5:n.784G>A, ENST00000553106.5:c.688G>A, NM_000277.1(PAH):c.688G>A (p.Val230Ile) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [Unmet], PP4-Moderate [MET], PM5 [Unmet], PM3-Very Strong [MET], PP3 [Unmet], PS3 [Unmet] PAH-specific ACMG/AMP criteria applied: PP4_Moderate: V2301 seen in 1 patient with PAH deficiency. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_VeryStrong: Detected in trans with IVS 10-11G>A, L48S, R408W, E390G). Upgraded per ClinGen SVI Workgroup. (PMID:15943553; PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_VeryStrong). 8268925, 21147011, 15943553, 11161839, 17924342 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-12 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA286506/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103248897 102792 C A NM_000277.2(PAH):c.706+17G>T 102792 CA229702 NM_000277.2:c.706+17G>T, NC_000012.12:g.102855119C>A, CM000674.2:g.102855119C>A, NC_000012.11:g.103248897C>A, CM000674.1:g.103248897C>A, NC_000012.10:g.101773027C>A, NG_008690.1:g.67484G>T, NG_008690.2:g.108292G>T, NM_000277.1:c.706+17G>T, XM_011538422.1:c.706+17G>T, NM_001354304.1:c.706+17G>T, XM_017019370.2:c.706+17G>T, NM_000277.3:c.706+17G>T, ENST00000307000.7:c.691+17G>T, ENST00000549111.5:n.819G>T, ENST00000553106.5:c.706+17G>T, NM_000277.2(PAH):c.706+17G>T PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Benign BS1 [MET], PP4 [Unmet], BP4 [MET] The c.706+17G>T variant in PAH has been reported in the mother of a patient with PKU (not found in the patient). PMID: 11139255. The MAF for this variant is 0.00269, greater than expected. Multiple splicing predictors suggest no impact (HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. MaxEnt: +15.3 % variation). In summary, this variant meets criteria to be classified as likely benign: BS1, BP4. 11139255 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229702/MONDO:0009861/006 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246735 102795 T A NM_000277.2(PAH):c.707-7A>T 102795 CA180267 NM_000277.2:c.707-7A>T, NM_000277.1:c.707-7A>T, XM_011538422.1:c.707-7A>T, NM_001354304.1:c.707-7A>T, NM_000277.3:c.707-7A>T, ENST00000307000.7:c.692-7A>T, ENST00000549247.6:n.459A>T, ENST00000553106.5:c.707-7A>T, NC_000012.12:g.102852957T>A, CM000674.2:g.102852957T>A, NC_000012.11:g.103246735T>A, CM000674.1:g.103246735T>A, NC_000012.10:g.101770865T>A, NG_008690.1:g.69646A>T, NG_008690.2:g.110454A>T, NM_000277.2(PAH):c.707-7A>T PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Benign BP4 [MET], BA1 [MET] PAH-specific ACMG/AMP criteria applied: BA1: Highest MAF=0.10514 in 1000G. 35 homozygotes in ExAC; BP4: HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. CADD=1.163344. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1, BP4). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA180267/MONDO:0009861/006 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 12 103246714 102803 G A NM_000277.1(PAH):c.721C>T (p.Arg241Cys) 102803 CA273357 NM_000277.1:c.721C>T, NC_000012.12:g.102852936G>A, CM000674.2:g.102852936G>A, NC_000012.11:g.103246714G>A, CM000674.1:g.103246714G>A, NC_000012.10:g.101770844G>A, NG_008690.1:g.69667C>T, NG_008690.2:g.110475C>T, XM_011538422.1:c.721C>T, NM_000277.2:c.721C>T, NM_001354304.1:c.721C>T, NM_000277.3:c.721C>T, ENST00000307000.7:c.706C>T, ENST00000549247.6:n.480C>T, ENST00000553106.5:c.721C>T, NM_000277.1(PAH):c.721C>T (p.Arg241Cys) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET], PS3 [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (0.00014) and gnomAD (0.0001301); PP3: Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster; PP4_Moderate: Seen in multiple PKU patients. BH4 deficiency excluded in 2 patients. Upgraded per ClinGen Metabolic Workgroup. (PMID:8222245; PMID:11142755); PM3_Strong: R241C seen once in trans with R413P, and once with R243Q, both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:11142755); PS3: In vitro PAH R241C mutant was found to have 25% PAH activity of normal. In vivo phenylalanine breath test measured a decreased level in R241C homozygote. (PMID:15319459; PMID:7915167). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong, PS3). 11142755, 8222245, 7915167, 15319459, 11142755 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273357/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246713 102804 C T NM_000277.1(PAH):c.722G>A (p.Arg241His) 102804 CA286507 NM_000277.1:c.722G>A, NC_000012.12:g.102852935C>T, CM000674.2:g.102852935C>T, NC_000012.11:g.103246713C>T, CM000674.1:g.103246713C>T, NC_000012.10:g.101770843C>T, NG_008690.1:g.69668G>A, NG_008690.2:g.110476G>A, XM_011538422.1:c.722G>A, NM_000277.2:c.722G>A, NM_001354304.1:c.722G>A, NM_000277.3:c.722G>A, ENST00000307000.7:c.707G>A, ENST00000549247.6:n.481G>A, ENST00000553106.5:c.722G>A, NM_000277.1(PAH):c.722G>A (p.Arg241His) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [MET], PP3 [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC, gnomAD, 1000G, ESP (0.000077- 0.0001518); PP3: Predicted deleterious in SIFT, PolyPhen2, MutationTaster; PM5: R241C (VarID 102803) is Pathogenic in ClinVar based on 3 submitters; PP4_Moderate: R241H seen in 1 PKU patient. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_Strong: R241H detected in trans with pathogenic variants (IVS10, R408W, R252W). Upgraded per ClinGen SVI Workgroup. (PMID:9429153). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM5, PP4_Moderate, PM3_Strong). 8268925, 9429153 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA286507/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103246696 102815 C T NM_000277.2(PAH):c.739G>A (p.Gly247Ser) 102815 CA229730 NM_000277.2:c.739G>A, NM_000277.1:c.739G>A, XM_011538422.1:c.739G>A, NM_001354304.1:c.739G>A, NM_000277.3:c.739G>A, ENST00000307000.7:c.724G>A, ENST00000549247.6:n.498G>A, ENST00000553106.5:c.739G>A, NC_000012.12:g.102852918C>T, CM000674.2:g.102852918C>T, NC_000012.11:g.103246696C>T, CM000674.1:g.103246696C>T, NC_000012.10:g.101770826C>T, NG_008690.1:g.69685G>A, NG_008690.2:g.110493G>A, NM_000277.2(PAH):c.739G>A (p.Gly247Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3 [MET], PP3 [MET] The c.739G>A (p.Gly247Ser) variant in PAH was reported in 1 patient with classical PKU, BH4 deficiency excluded. (PMID: 16256386, 25456745) It was detected with T200Nfs, (pathogenic per PAH VCEP). This variant is absent from ExAC, 1000G, gnomAD, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.981. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3. 25456745, 16256386, 25456745 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229730/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246696 102816 C G NM_000277.2(PAH):c.739G>C (p.Gly247Arg) 102816 CA229732 NM_000277.2:c.739G>C, NC_000012.12:g.102852918C>G, CM000674.2:g.102852918C>G, NC_000012.11:g.103246696C>G, CM000674.1:g.103246696C>G, NC_000012.10:g.101770826C>G, NG_008690.1:g.69685G>C, NG_008690.2:g.110493G>C, NM_000277.1:c.739G>C, XM_011538422.1:c.739G>C, NM_001354304.1:c.739G>C, NM_000277.3:c.739G>C, ENST00000307000.7:c.724G>C, ENST00000549247.6:n.498G>C, ENST00000553106.5:c.739G>C, NM_000277.2(PAH):c.739G>C (p.Gly247Arg) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET], PM3-Strong [MET] The c.739G>C (p.Gly247Arg) variant in PAH has been reported in 3 patients with PAH deficiency, with BH4 deficiency assessed in 2 patients. PMID: 21307867, 18985011, 16256386. It was detected with known pathogenic variants R413P (PMID: 16256386) and V388M (PMID: 18985011). It was absent from ExAC, gnomAD, 1000G, and ESP. This variant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.981. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3. 21307867, 18985011, 16256386, 18985011, 16256386 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229732/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246695 102817 C T NM_000277.2(PAH):c.740G>A (p.Gly247Asp) 102817 CA229734 NM_000277.2:c.740G>A, NM_000277.1:c.740G>A, XM_011538422.1:c.740G>A, NM_001354304.1:c.740G>A, NM_000277.3:c.740G>A, ENST00000307000.7:c.725G>A, ENST00000549247.6:n.499G>A, ENST00000553106.5:c.740G>A, NC_000012.12:g.102852917C>T, CM000674.2:g.102852917C>T, NC_000012.11:g.103246695C>T, CM000674.1:g.103246695C>T, NC_000012.10:g.101770825C>T, NG_008690.1:g.69686G>A, NG_008690.2:g.110494G>A, NM_000277.2(PAH):c.740G>A (p.Gly247Asp) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [Unmet], PP3 [MET], PP4 [MET] The c.740G>A (p.Gly247Asp) variant in PAH was reported in 2 patients with classic PKU. PMID: 20920871. This varant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.975. It has an extremely low frequency in ExAC/gnomAD (MAF 0.00003). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PP3. 20920871 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229734/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103246690 102821 G A NM_000277.2(PAH):c.745C>T (p.Leu249Phe) 102821 CA273356 NM_000277.2:c.745C>T, NC_000012.12:g.102852912G>A, CM000674.2:g.102852912G>A, NC_000012.11:g.103246690G>A, CM000674.1:g.103246690G>A, NC_000012.10:g.101770820G>A, NG_008690.1:g.69691C>T, NG_008690.2:g.110499C>T, NM_000277.1:c.745C>T, XM_011538422.1:c.745C>T, NM_001354304.1:c.745C>T, NM_000277.3:c.745C>T, ENST00000307000.7:c.730C>T, ENST00000549247.6:n.504C>T, ENST00000553106.5:c.745C>T, NM_000277.2(PAH):c.745C>T (p.Leu249Phe) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3-Very Strong [MET], PP3 [MET], PS3 [Unmet] PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD (0.00004065); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.981; PP4_Moderate: L249F was seen 3 times in HPA patients associated with 2 different haplotypes. DHPR defeciency was excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:8533759); PM3_VeryStrong: Seen with R261X, A309V, V388M, R261Q. All Pathogenic/Likely Pathogenic in ClinVar. Upgraded per ClinGen SVI Workgroup (PMID:21871829; PMID:24765287). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_VeryStrong). 8533759, 24765287, 21871829 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-12 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273356/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246681 102823 G C NM_000277.1(PAH):c.754C>G (p.Arg252Gly) 102823 CA229742 NM_000277.1:c.754C>G, XM_011538422.1:c.754C>G, NM_000277.2:c.754C>G, NM_001354304.1:c.754C>G, NM_000277.3:c.754C>G, ENST00000307000.7:c.739C>G, ENST00000549247.6:n.513C>G, ENST00000553106.5:c.754C>G, NC_000012.12:g.102852903G>C, CM000674.2:g.102852903G>C, NC_000012.11:g.103246681G>C, CM000674.1:g.103246681G>C, NC_000012.10:g.101770811G>C, NG_008690.1:g.69700C>G, NG_008690.2:g.110508C>G, NM_000277.1(PAH):c.754C>G (p.Arg252Gly) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [MET], PP3 [MET], PS3 [MET] The c.754C>G (p.Arg252Gly) variant in PAH has been reported in multiple individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 1363786, 9634518). This variant is absent in population databases (PM2). This variant has 3% enzyme activity (PS3; PMID: 9799096). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). This missense change is at an amino acid residue where different pathogenic missense changes have been seen before (p.Arg252Gln/Trp). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM5, PP3. 1363786, 9634518, 9799096 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-08 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229742/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246680 102824 C T NM_000277.1(PAH):c.755G>A (p.Arg252Gln) 102824 CA229743 NM_000277.1:c.755G>A, NC_000012.12:g.102852902C>T, CM000674.2:g.102852902C>T, NC_000012.11:g.103246680C>T, CM000674.1:g.103246680C>T, NC_000012.10:g.101770810C>T, NG_008690.1:g.69701G>A, NG_008690.2:g.110509G>A, XM_011538422.1:c.755G>A, NM_000277.2:c.755G>A, NM_001354304.1:c.755G>A, NM_000277.3:c.755G>A, ENST00000307000.7:c.740G>A, ENST00000549247.6:n.514G>A, ENST00000553106.5:c.755G>A, NM_000277.1(PAH):c.755G>A (p.Arg252Gln) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET], PS3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: ; PP3: tools predict damaging; PS3: BioPKU 3% enzyme activity; 3.8% residual activity (PMID:24401910); PM3: Detected in trans with p.Pro407fs (PMID:7833954); PP4_Moderate: Detected in 2 patients with classic PKU (Phe>1.5mM). BH4 deficiency excluded (PMID:7833954; PMID:9634518). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate). 9634518, 7833954, 7833954, 24401910 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229743/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246653 102832 C G NM_000277.1(PAH):c.782G>C (p.Arg261Pro) 102832 CA229759 NM_000277.1:c.782G>C, NC_000012.12:g.102852875C>G, CM000674.2:g.102852875C>G, NC_000012.11:g.103246653C>G, CM000674.1:g.103246653C>G, NC_000012.10:g.101770783C>G, NG_008690.1:g.69728G>C, NG_008690.2:g.110536G>C, XM_011538422.1:c.782G>C, NM_000277.2:c.782G>C, NM_001354304.1:c.782G>C, NM_000277.3:c.782G>C, ENST00000307000.7:c.767G>C, ENST00000549247.6:n.541G>C, ENST00000553106.5:c.782G>C, NM_000277.1(PAH):c.782G>C (p.Arg261Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PM5 [MET], PP4 [MET], PP3 [MET], PM3-Strong [MET] The PAH c.782G>C (p.Arg261Pro) variant has been reported in multiple affected individuals (PMID: 26666653, Bh4 deficiency not ruled out, PP4). It has been detected with 5 known pathogenic variants (PM3_S). It is absent from ExAC/gnomAD. Computational evidence supports a deleterious effect. Also, p.R261Q is interpreted as pathogenic. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_S, PM2, PM5, PP4, PP3. 26666653, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229759/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246646 102833 G C NM_000277.2(PAH):c.789C>G (p.Phe263Leu) 102833 CA229760 NM_000277.2:c.789C>G, NM_000277.1:c.789C>G, XM_011538422.1:c.789C>G, NM_001354304.1:c.789C>G, NM_000277.3:c.789C>G, ENST00000307000.7:c.774C>G, ENST00000549247.6:n.548C>G, ENST00000553106.5:c.789C>G, NC_000012.12:g.102852868G>C, CM000674.2:g.102852868G>C, NC_000012.11:g.103246646G>C, CM000674.1:g.103246646G>C, NC_000012.10:g.101770776G>C, NG_008690.1:g.69735C>G, NG_008690.2:g.110543C>G, NM_000277.2(PAH):c.789C>G (p.Phe263Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3 [Unmet], PP3 [MET] The c.789C>G (p.Phe263Leu) variant in PAH is reported in 1 patient with classical PKU, and 1 Chinese PKU patient. (BH4 deficiency excluded. PMID: 8222245, 26600521) This variant is absent from 1000G and ESP with extremely low frequency in ExAC/gnomAD (MAF=0.00003). It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.929. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3. 26600521, 8222245, 26600521 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229760/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103246636 102839 G C NM_000277.2(PAH):c.799C>G (p.Gln267Glu) 102839 CA229769 NM_000277.2:c.799C>G, NC_000012.12:g.102852858G>C, CM000674.2:g.102852858G>C, NC_000012.11:g.103246636G>C, CM000674.1:g.103246636G>C, NC_000012.10:g.101770766G>C, NG_008690.1:g.69745C>G, NG_008690.2:g.110553C>G, NM_000277.1:c.799C>G, XM_011538422.1:c.799C>G, NM_001354304.1:c.799C>G, NM_000277.3:c.799C>G, ENST00000307000.7:c.784C>G, ENST00000549247.6:n.558C>G, ENST00000553106.5:c.799C>G, NM_000277.2(PAH):c.799C>G (p.Gln267Glu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PM5 [Unmet], PM3 [MET], PP3 [MET], PP4 [MET], PS3 [MET] The c.799C>G (p.Gln267Glu) variant in PAH was reported in 2 Chinese PKU patients. BH4 deficiencies not completely ruled out. (PMID: 26600521) This variant was detected with known pathogenic variants p.R111X (PMID: 16256386), and D101N (not in ClinVar, PMID: 26600521). It is absent from ExAC, gnomAD, 1000G, and ESP. This variant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.935. This variant was expressed in e. coli using a rat Q267E mutant. It has 11% activity of wt. based on duplicate determinations of a single clone. (PMID: 7914195). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PS3, PP3, PP4. 26600521, 16256386, 26600521, 16256386, 9450897, 7914195 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229769/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246634 102840 C G NM_000277.2(PAH):c.801G>C (p.Gln267His) 102840 CA229771 NM_000277.2:c.801G>C, NM_000277.1:c.801G>C, XM_011538422.1:c.801G>C, NM_001354304.1:c.801G>C, NM_000277.3:c.801G>C, ENST00000307000.7:c.786G>C, ENST00000549247.6:n.560G>C, ENST00000553106.5:c.801G>C, NC_000012.12:g.102852856C>G, CM000674.2:g.102852856C>G, NC_000012.11:g.103246634C>G, CM000674.1:g.103246634C>G, NC_000012.10:g.101770764C>G, NG_008690.1:g.69747G>C, NG_008690.2:g.110555G>C, NM_000277.2(PAH):c.801G>C (p.Gln267His) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM5 [Unmet], PM3 [MET], PP3 [MET], PP4 [MET] The c.801G>C (p.Gln267His) variant in PAH has been reported in 1 Chinese patient with classical PKU. BH4 deficiencies were not assessed. PMID: 16256386, 19915519. It was detected with a known pathogenic variant p.R252Q. PMID: 16256386. It is absent from population databases. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.952. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. 16256386, 19915519, 16256386 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229771/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246633 102841 A G NM_000277.2(PAH):c.802T>C (p.Tyr268His) 102841 CA229773 NM_000277.2:c.802T>C, NC_000012.12:g.102852855A>G, CM000674.2:g.102852855A>G, NC_000012.11:g.103246633A>G, CM000674.1:g.103246633A>G, NC_000012.10:g.101770763A>G, NG_008690.1:g.69748T>C, NG_008690.2:g.110556T>C, NM_000277.1:c.802T>C, XM_011538422.1:c.802T>C, NM_001354304.1:c.802T>C, NM_000277.3:c.802T>C, ENST00000307000.7:c.787T>C, ENST00000549247.6:n.561T>C, ENST00000553106.5:c.802T>C, NM_000277.2(PAH):c.802T>C (p.Tyr268His) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [Unmet], PP3 [MET] The c.802T>C (p.Tyr268His) variant in PAH has not been reported in the literature to our knowledge. The reference in BioPKU/PAHdb (Eisensmith, 1996) does not include this variant. It is absent from ExAC, 1000G, and ESP, with Extremely low frequency in gnomAD (0.000004063). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.977. . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229773/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246630 102842 T G NM_000277.1(PAH):c.805A>C (p.Ile269Leu) 102842 CA229775 NM_000277.1:c.805A>C, NC_000012.12:g.102852852T>G, CM000674.2:g.102852852T>G, NC_000012.11:g.103246630T>G, CM000674.1:g.103246630T>G, NC_000012.10:g.101770760T>G, NG_008690.1:g.69751A>C, NG_008690.2:g.110559A>C, XM_011538422.1:c.805A>C, NM_000277.2:c.805A>C, NM_001354304.1:c.805A>C, NM_000277.3:c.805A>C, ENST00000307000.7:c.790A>C, ENST00000549247.6:n.564A>C, ENST00000553106.5:c.805A>C, NM_000277.1(PAH):c.805A>C (p.Ile269Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM3-Very Strong [MET], PP3 [MET] The c.805A>C (p.Ile269Leu) variant in PAH has been reported in multiple individuals with PAH deficiency, including non-PKU HPA (BH4 deficiency excluded). (PP4_Moderate; PMID10767174, PMID 2350059). This variant has an extremely low allele frequency in ExAC and gnomAD (PM2; ENF=0.00013). This variant was detected in trans with multiple known pathogenic variants: PMID 9521426: c.842+3G>C; PMID 10767174: R261X; PMID 14726806: E280K; PMID 21871829: IVS10-11G>A (PM3_Very-strong). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Very-strong, PP4_Moderate, PM2, PP3. 10767174, 9521426, 14726806, 10767174, 9521426, 21871829 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229775/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246628 102844 GA G NM_000277.2(PAH):c.806delT (p.Ile269Thrfs) 102844 CA229778 NM_000277.2:c.806delT, NM_000277.1:c.806del, XM_011538422.1:c.806del, NM_000277.2:c.806del, NM_001354304.1:c.806del, NM_000277.3:c.806del, ENST00000307000.7:c.791del, ENST00000549247.6:n.565del, ENST00000553106.5:c.806del, NC_000012.12:g.102852851del, CM000674.2:g.102852851del, NC_000012.11:g.103246629del, CM000674.1:g.103246629del, NC_000012.10:g.101770759del, NG_008690.1:g.69752del, NG_008690.2:g.110560del, NM_000277.2(PAH):c.806delT (p.Ile269Thrfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. gnomAD MAF=0.00007.; PP4: Detected in a PKU patient. BH4 deficiency not assessed. (PMID:9012412). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4). 9012412 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229778/MONDO:0009861/006 0.9971 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246624 102849 G A NM_000277.2(PAH):c.811C>T (p.His271Tyr) 102849 CA229784 NM_000277.2:c.811C>T, NC_000012.12:g.102852846G>A, CM000674.2:g.102852846G>A, NC_000012.11:g.103246624G>A, CM000674.1:g.103246624G>A, NC_000012.10:g.101770754G>A, NG_008690.1:g.69757C>T, NG_008690.2:g.110565C>T, NM_000277.1:c.811C>T, XM_011538422.1:c.811C>T, NM_001354304.1:c.811C>T, NM_000277.3:c.811C>T, ENST00000307000.7:c.796C>T, ENST00000549247.6:n.570C>T, ENST00000553106.5:c.811C>T, NM_000277.2(PAH):c.811C>T (p.His271Tyr) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [Unmet], PP3 [MET], PP4 [MET] The c.811C>T (p.His271Tyr) variant in PAH has been reported in 2 unrelated PKU patients. BH4 deficiencies not assessed. (PMID: 9012412) A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.978. This variant has an extremely low frequency in ExAC, 1000G, ESP, and gnomAD (MAF=0.00001). . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4. 9012412 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229784/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103246623 102850 T C NM_000277.2(PAH):c.812A>G (p.His271Arg) 102850 CA286508 NM_000277.2:c.812A>G, NM_000277.1:c.812A>G, XM_011538422.1:c.812A>G, NM_001354304.1:c.812A>G, NM_000277.3:c.812A>G, ENST00000307000.7:c.797A>G, ENST00000549247.6:n.571A>G, ENST00000553106.5:c.812A>G, NC_000012.12:g.102852845T>C, CM000674.2:g.102852845T>C, NC_000012.11:g.103246623T>C, CM000674.1:g.103246623T>C, NC_000012.10:g.101770753T>C, NG_008690.1:g.69758A>G, NG_008690.2:g.110566A>G, NM_000277.2(PAH):c.812A>G (p.His271Arg) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3 [MET], PP3 [MET] The c.812A>G (p.His271Arg) variant in the PAH gene has been reported in PKU patients in Henan, and France. Dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading were collected for the Chinese patient. (PMID: 21462123, 26666653, 26503515). This variant was detected with R408W (PMID: 26666653). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.969. It has an extremely low frequency in ExAC and gnomAD (MAF=0.00006). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PP3. 26503515, 26666653, 21462123, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA286508/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246615 102851 T C NM_000277.2(PAH):c.820A>G (p.Lys274Glu) 102851 CA229786 NM_000277.2:c.820A>G, NM_000277.1:c.820A>G, XM_011538422.1:c.820A>G, NM_001354304.1:c.820A>G, NM_000277.3:c.820A>G, ENST00000307000.7:c.805A>G, ENST00000549247.6:n.579A>G, ENST00000553106.5:c.820A>G, NC_000012.12:g.102852837T>C, CM000674.2:g.102852837T>C, NC_000012.11:g.103246615T>C, CM000674.1:g.103246615T>C, NC_000012.10:g.101770745T>C, NG_008690.1:g.69766A>G, NG_008690.2:g.110574A>G, NM_000277.2(PAH):c.820A>G (p.Lys274Glu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Benign BS1 [MET], PM5 [Unmet], PP3 [Unmet], BS3-Supporting [MET] PAH-specific ACMG/AMP criteria applied: BS1: MAF= 0.01815 in 1000G. 2 homozygotes in ExAC, 1 homozygote in 1000G.; BS3_Supporting: Enzyme activity of K274E is indistinguishable from that of the wild-type protein. Detailed kinetic analyses of PAH expressed in E. coli showed that the K274E mutant protein has kinetic properties similar to that of the wild-type protein. (PMID:11461196). In summary this variant meets criteria to be classified as likely benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BS3_Supporting). 11461196 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229786/MONDO:0009861/006 0.1 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 12 103246612 102853 G A NM_000277.2(PAH):c.823C>T (p.Pro275Ser) 102853 CA229789 NM_000277.2:c.823C>T, NC_000012.12:g.102852834G>A, CM000674.2:g.102852834G>A, NC_000012.11:g.103246612G>A, CM000674.1:g.103246612G>A, NC_000012.10:g.101770742G>A, NG_008690.1:g.69769C>T, NG_008690.2:g.110577C>T, NM_000277.1:c.823C>T, XM_011538422.1:c.823C>T, NM_001354304.1:c.823C>T, NM_000277.3:c.823C>T, ENST00000307000.7:c.808C>T, ENST00000549247.6:n.582C>T, ENST00000553106.5:c.823C>T, NM_000277.2(PAH):c.823C>T (p.Pro275Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [MET], PP3 [MET], PM3-Strong [MET] The c.823C>T (p.Pro275Ser) variant in PAH is absent from all population databases, and is in the same codon as two other likely pathogenic variants. In silico algorithms agree on a damaging effect. It has been identified in trans with two independent pathogenic variants (R408W and c.669delC; PMID: 20123475, 24705691), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in multiple patients. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PM5, PP3. 20123475, 24705691, 20123475, 24705691 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229789/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246611 102854 G C NM_000277.2(PAH):c.824C>G (p.Pro275Arg) 102854 CA229791 NM_000277.2:c.824C>G, NM_000277.1:c.824C>G, XM_011538422.1:c.824C>G, NM_001354304.1:c.824C>G, NM_000277.3:c.824C>G, ENST00000307000.7:c.809C>G, ENST00000549247.6:n.583C>G, ENST00000553106.5:c.824C>G, NC_000012.12:g.102852833G>C, CM000674.2:g.102852833G>C, NC_000012.11:g.103246611G>C, CM000674.1:g.103246611G>C, NC_000012.10:g.101770741G>C, NG_008690.1:g.69770C>G, NG_008690.2:g.110578C>G, NM_000277.2(PAH):c.824C>G (p.Pro275Arg) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PM5 [MET], PP3 [MET] The c.824C>G (p.Pro275Arg) variant in PAH is absent from population databases and predicted deleterious by multiple in silico algorithms. It is in the same codon as two previously reported likely pathogenic variants (p.Pro275Ser and p.Pro275Leu). It has been identified in trans with a pathogenic variant (PMID: 23514811), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in that patient. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PM5, PP3. 23514811, 23514811 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229791/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246609 102856 T C NM_000277.2(PAH):c.826A>G (p.Met276Val) 102856 CA229794 NM_000277.2:c.826A>G, NM_000277.1:c.826A>G, XM_011538422.1:c.826A>G, NM_001354304.1:c.826A>G, NM_000277.3:c.826A>G, ENST00000307000.7:c.811A>G, ENST00000549247.6:n.585A>G, ENST00000553106.5:c.826A>G, NC_000012.12:g.102852831T>C, CM000674.2:g.102852831T>C, NC_000012.11:g.103246609T>C, CM000674.1:g.103246609T>C, NC_000012.10:g.101770739T>C, NG_008690.1:g.69772A>G, NG_008690.2:g.110580A>G, NM_000277.2(PAH):c.826A>G (p.Met276Val) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [Unmet], PM3-Strong [MET] The c.826A>G (p.Met276Val) variant in PAH is absent from population databases. It has been identified in trans with pathogenic variants in two patients (A300S and R261Q; PMID: 16198137), and identified in an additional patient in which a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 9634518). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. 9634518, 16198137 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229794/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246608 102857 A T NM_000277.2(PAH):c.827T>A (p.Met276Lys) 102857 CA229795 NM_000277.2:c.827T>A, NC_000012.12:g.102852830A>T, CM000674.2:g.102852830A>T, NC_000012.11:g.103246608A>T, CM000674.1:g.103246608A>T, NC_000012.10:g.101770738A>T, NG_008690.1:g.69773T>A, NG_008690.2:g.110581T>A, NM_000277.1:c.827T>A, XM_011538422.1:c.827T>A, NM_001354304.1:c.827T>A, NM_000277.3:c.827T>A, ENST00000307000.7:c.812T>A, ENST00000549247.6:n.586T>A, ENST00000553106.5:c.827T>A, NM_000277.2(PAH):c.827T>A (p.Met276Lys) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PM5 [MET], PP3 [Unmet] The c.827T>A (p.Met276Lys) variant in PAH is absent from population databases, and found in the same codon as a previously reported pathogenic variant (p.Met276Val). It has been identified in trans with a known pathogenic variant (I95del), in which a defect of BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 25894915). 25894915, 25894915 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229795/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246608 102858 A C NM_000277.2(PAH):c.827T>G (p.Met276Arg) 102858 CA229797 NM_000277.2:c.827T>G, NM_000277.1:c.827T>G, XM_011538422.1:c.827T>G, NM_001354304.1:c.827T>G, NM_000277.3:c.827T>G, ENST00000307000.7:c.812T>G, ENST00000549247.6:n.586T>G, ENST00000553106.5:c.827T>G, NC_000012.12:g.102852830A>C, CM000674.2:g.102852830A>C, NC_000012.11:g.103246608A>C, CM000674.1:g.103246608A>C, NC_000012.10:g.101770738A>C, NG_008690.1:g.69773T>G, NG_008690.2:g.110581T>G, NM_000277.2(PAH):c.827T>G (p.Met276Arg) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM5 [MET], PP3 [MET], PP4 [MET] The c.827T>G (p.Met276Arg) variant in PAH is absent from population databases and predicted damaging by in silico models. It is a novel missense change at an amino acid residue where different pathogenic missense changes have been reported (p.Met276Val is LP in ClinVar, p.Met276Lys is LP via PAH EP). It has been reported in individuals with phenylkeonuria in the literature, although a defect in the metabolism of BH4 has not been excluded as a cause for elevated phenylalanine in any of these patients (PMID: 23932990, 15300621). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM5, PP3. 15300621, 23932990 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229797/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103246592 102869 C A NM_000277.2(PAH):c.842+1G>T 102869 CA229812 NM_000277.2:c.842+1G>T, NC_000012.12:g.102852814C>A, CM000674.2:g.102852814C>A, NC_000012.11:g.103246592C>A, CM000674.1:g.103246592C>A, NC_000012.10:g.101770722C>A, NG_008690.1:g.69789G>T, NG_008690.2:g.110597G>T, NM_000277.1:c.842+1G>T, XM_011538422.1:c.842+1G>T, NM_001354304.1:c.842+1G>T, NM_000277.3:c.842+1G>T, ENST00000307000.7:c.827+1G>T, ENST00000549247.6:n.601+1G>T, ENST00000553106.5:c.842+1G>T, ENST00000635477.1:n.3+1G>T, NM_000277.2(PAH):c.842+1G>T PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] The PAH c.842+1G>T variant has been reported at least once in the literature in a 15 month old patient with moderate PKU in the homozygote state (PP4, PMID: 23220018). This variant is absent from 1000G, ESP, and gnomAD databases. This variant disrupts the canonical splice donor site of intron 7 where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 7 is present in biologically-relevant transcript. In summary, this variant meets criteria to be pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PVS1. 23220018 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229812/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246590 102871 C G NM_000277.2(PAH):c.842+3G>C 102871 CA229814 NM_000277.2:c.842+3G>C, NM_000277.1:c.842+3G>C, XM_011538422.1:c.842+3G>C, NM_001354304.1:c.842+3G>C, NM_000277.3:c.842+3G>C, ENST00000307000.7:c.827+3G>C, ENST00000549247.6:n.601+3G>C, ENST00000553106.5:c.842+3G>C, ENST00000635477.1:n.3+3G>C, NC_000012.12:g.102852812C>G, CM000674.2:g.102852812C>G, NC_000012.11:g.103246590C>G, CM000674.1:g.103246590C>G, NC_000012.10:g.101770720C>G, NG_008690.1:g.69791G>C, NG_008690.2:g.110599G>C, NM_000277.2(PAH):c.842+3G>C PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3-Strong [MET] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in gnomAD+ExAC (MAF=0.00006). Absent from 1000G, ESP.; PP4_Moderate: Detected in Costa Rican and 1 Spanish PKU patients, exclusion of defects in tetrahydrobiopterine metabolism. (PMID:8860005; PMID:8981952); PM3_Strong: Detected in trans with I269L and R408W, known pathogenic variants. (PMID:9521426; PMID:23430918). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). 8860005, 8981952, 23430918, 9521426 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-09-11 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229814/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245536 102873 T A NM_000277.2(PAH):c.843-2A>T 102873 CA229816 NM_000277.2:c.843-2A>T, NM_000277.1:c.843-2A>T, XM_011538422.1:c.843-2A>T, NM_001354304.1:c.843-2A>T, NM_000277.3:c.843-2A>T, ENST00000307000.7:c.828-2A>T, ENST00000549247.6:n.602-2A>T, ENST00000551114.2:n.503A>T, ENST00000553106.5:c.843-2A>T, ENST00000635477.1:n.4-2A>T, NC_000012.12:g.102851758T>A, CM000674.2:g.102851758T>A, NC_000012.11:g.103245536T>A, CM000674.1:g.103245536T>A, NC_000012.10:g.101769666T>A, NG_008690.1:g.70845A>T, NG_008690.2:g.111653A>T, NM_000277.2(PAH):c.843-2A>T PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [Unmet], PP4 [MET] The c.843-2A>T variant in PAH has been reported in 1 homozygote individual with classic PKU (PMID: 9452062). This variant disrupts the canonical splice acceptor site of intron 8 where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 8 is present in biologically-relevant transcript. This variant is absent from population databases, including: 1000 Genomes, ESP, and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229816/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245529 102877 A T NM_000277.2(PAH):c.848T>A (p.Ile283Asn) 102877 CA229821 NM_000277.2:c.848T>A, NC_000012.12:g.102851751A>T, CM000674.2:g.102851751A>T, NC_000012.11:g.103245529A>T, CM000674.1:g.103245529A>T, NC_000012.10:g.101769659A>T, NG_008690.1:g.70852T>A, NG_008690.2:g.111660T>A, NM_000277.1:c.848T>A, XM_011538422.1:c.848T>A, NM_001354304.1:c.848T>A, NM_000277.3:c.848T>A, ENST00000307000.7:c.833T>A, ENST00000549247.6:n.607T>A, ENST00000551114.2:n.510T>A, ENST00000553106.5:c.848T>A, ENST00000635477.1:n.9T>A, NM_000277.2(PAH):c.848T>A (p.Ile283Asn) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [MET], PP3 [MET], PM3-Strong [MET] The c.848T>A (p.Ile283Asn) variant in PAH is absent from population databases and predicted damaging with in silico predictors. It is a novel missense change in a residue where a different pathogenic variant has been identified (c.847A>T (p.Ile283Phe). It has been identified in multiple affected individuals in trans with known pathogenic variants (PMID: 9521426, 26413448), and was identified in a patient in which a defect in BH4 metabolism had been excluded. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3. 26413448, 9521426 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229821/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245521 102880 C T NM_000277.2(PAH):c.856G>A (p.Glu286Lys) 102880 CA229826 NM_000277.2:c.856G>A, NC_000012.12:g.102851743C>T, CM000674.2:g.102851743C>T, NC_000012.11:g.103245521C>T, CM000674.1:g.103245521C>T, NC_000012.10:g.101769651C>T, NG_008690.1:g.70860G>A, NG_008690.2:g.111668G>A, NM_000277.1:c.856G>A, XM_011538422.1:c.856G>A, NM_001354304.1:c.856G>A, NM_000277.3:c.856G>A, ENST00000307000.7:c.841G>A, ENST00000549247.6:n.615G>A, ENST00000551114.2:n.518G>A, ENST00000553106.5:c.856G>A, ENST00000635477.1:n.17G>A, NM_000277.2(PAH):c.856G>A (p.Glu286Lys) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET], PS3 [MET] The c.856G>A (p.Glu286Lys) variant in PAH is present with low frequency in population databases (1.2e-4), and is predicted to be deleterious using in silico algorithms. It has been identified in trans with pathogenic variants in two independent patients (R243Q, R241C), and has been identified in a patients with Phenylketonuria in which a defect in BH4 metabolism has been excluded (PMID: 14722928, 24401910). Enzyme activity has been measured as 1% of wild type controls (BioPKU). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PS3, PP3. 24401910, 14722928, 14722928 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229826/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245513 102881 C G NM_000277.2(PAH):c.864G>C (p.Leu288Phe) 102881 CA229828 NM_000277.2:c.864G>C, NM_000277.1:c.864G>C, XM_011538422.1:c.864G>C, NM_001354304.1:c.864G>C, NM_000277.3:c.864G>C, ENST00000307000.7:c.849G>C, ENST00000549247.6:n.623G>C, ENST00000551114.2:n.526G>C, ENST00000553106.5:c.864G>C, ENST00000635477.1:n.25G>C, NC_000012.12:g.102851735C>G, CM000674.2:g.102851735C>G, NC_000012.11:g.103245513C>G, CM000674.1:g.103245513C>G, NC_000012.10:g.101769643C>G, NG_008690.1:g.70868G>C, NG_008690.2:g.111676G>C, NM_000277.2(PAH):c.864G>C (p.Leu288Phe) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP3 [MET], PP4 [MET] The c.864G>C (p.Leu288Phe) variant in PAH is absent from population databases, and in silico predictors suggest a damaging effect on protein function. It is listed in hPAHdb 2009 McGill, but there is no clinical information on any patient. To our current knowledge (December, 2018), this variant has not been previously reported in the literature. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229828/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245512 102882 C G NM_000277.2(PAH):c.865G>C (p.Gly289Arg) 102882 CA229830 NM_000277.2:c.865G>C, NC_000012.12:g.102851734C>G, CM000674.2:g.102851734C>G, NC_000012.11:g.103245512C>G, CM000674.1:g.103245512C>G, NC_000012.10:g.101769642C>G, NG_008690.1:g.70869G>C, NG_008690.2:g.111677G>C, NM_000277.1:c.865G>C, XM_011538422.1:c.865G>C, NM_001354304.1:c.865G>C, NM_000277.3:c.865G>C, ENST00000307000.7:c.850G>C, ENST00000549247.6:n.624G>C, ENST00000551114.2:n.527G>C, ENST00000553106.5:c.865G>C, ENST00000635477.1:n.26G>C, NM_000277.2(PAH):c.865G>C (p.Gly289Arg) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET], PS1 [MET] The c.865G>C (p.Gly289Arg) variant in PAH is absent from population databases and predicted deleterious with in silico prediction software. This is the same amnio acid change as a previously established pathogenic variant (c.865G>A; p.Gly289Arg). It has been identified in trans with a pathogenic variant (R155C, curated by the PAH EP), and a defect in BH4 metabolism was excluded (PMID: 22921945). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS1, PM2, PM3, PP3. 22921945, 23514811 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229830/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245493 102884 G C NM_000277.2(PAH):c.884C>G (p.Ser295Ter) 102884 CA229834 NM_000277.2:c.884C>G, NC_000012.12:g.102851715G>C, CM000674.2:g.102851715G>C, NC_000012.11:g.103245493G>C, CM000674.1:g.103245493G>C, NC_000012.10:g.101769623G>C, NG_008690.1:g.70888C>G, NG_008690.2:g.111696C>G, NM_000277.1:c.884C>G, XM_011538422.1:c.884C>G, NM_001354304.1:c.884C>G, NM_000277.3:c.884C>G, ENST00000307000.7:c.869C>G, ENST00000549247.6:n.643C>G, ENST00000551114.2:n.546C>G, ENST00000553106.5:c.884C>G, ENST00000635477.1:n.45C>G, NM_000277.2(PAH):c.884C>G (p.Ser295Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [Unmet], PP4 [MET] The c.884C>G (p.S295*) variant in PAH has been reported in 1 individual with PKU, however without indication of complete genotype (PMID:10394930). This variant is absent in population databases, including 1000 Genomes, Exome Sequencing Project (ESP) and the Genome Aggregation database (gnomAD). This is a nonsense variant in exon 8 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. Overall this variant meets criteria to be classified as pathogenic for PAH. ACMG/AMP criteria applied: PM2, PVS1, PP4. 10394930, 10394930 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229834/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245488 102885 G A NM_000277.2(PAH):c.889C>T (p.Arg297Cys) 102885 CA229836 NM_000277.2:c.889C>T, NC_000012.12:g.102851710G>A, CM000674.2:g.102851710G>A, NC_000012.11:g.103245488G>A, CM000674.1:g.103245488G>A, NC_000012.10:g.101769618G>A, NG_008690.1:g.70893C>T, NG_008690.2:g.111701C>T, NM_000277.1:c.889C>T, XM_011538422.1:c.889C>T, NM_001354304.1:c.889C>T, NM_000277.3:c.889C>T, ENST00000307000.7:c.874C>T, ENST00000549247.6:n.648C>T, ENST00000551114.2:n.551C>T, ENST00000553106.5:c.889C>T, ENST00000635477.1:n.50C>T, NM_000277.2(PAH):c.889C>T (p.Arg297Cys) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PM5 [MET], PP3 [MET] The c.889C>T (p.R297C) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded: PMID: 8807331, 21307867). It was detected in trans with the pathogenic variant IVS12nt1 (VarID576; PMID 8807331). This variant has an extremely low allele frequency in gnomAD (7/245782). Two other missense variants at the same codon are pathogenic. (92750). Computational prediction tools and conservation analysis suggest that the c.889C>T variant may impact the protein. Overall, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3, PM5, PP4_moderate. 8807331, 21307867, 8807331, 27121329 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229836/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245479 102886 CAAA C NM_000277.2(PAH):c.895_897delTTT (p.Phe299del) 102886 CA229837 NM_000277.2:c.895_897del, NM_000277.1:c.895_897del, XM_011538422.1:c.895_897del, NM_001354304.1:c.895_897del, NM_000277.3:c.895_897del, ENST00000307000.7:c.880_882del, ENST00000549247.6:n.654_656del, ENST00000551114.2:n.557_559del, ENST00000553106.5:c.895_897del, ENST00000635477.1:n.56_58del, NC_000012.12:g.102851702_102851704del, CM000674.2:g.102851702_102851704del, NC_000012.11:g.103245480_103245482del, CM000674.1:g.103245480_103245482del, NC_000012.10:g.101769610_101769612del, NG_008690.1:g.70899_70901del, NG_008690.2:g.111707_111709del, NM_000277.2(PAH):c.895_897delTTT (p.Phe299del) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM4 [MET], PP4 [MET] The c.895_897del (p.Phe299del) variant in PAH has been reported in 1 individual with PKU without genotype information (BH4 deficiency not ruled out) (PMID: 10541324) . This variant is absent in gnomAD and the ESP population databases. The c.895_897del variant results in an in-frame deletion of phenylalanine 299 in a hydrophobic pocket of the hydroxylase domain of PAH. In summary, this variant meets the criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM4. 10541324 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229837/MONDO:0009861/006 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245469 102888 GA G NM_000277.2(PAH):c.904delT (p.Ser303Profs) 102888 CA229840 NC_000012.12:g.102851695del, CM000674.2:g.102851695del, NC_000012.11:g.103245473del, CM000674.1:g.103245473del, NC_000012.10:g.101769603del, NG_008690.1:g.70911del, NG_008690.2:g.111719del, NM_000277.1:c.907del, XM_011538422.1:c.907del, NM_000277.2:c.907del, NM_001354304.1:c.907del, NM_000277.3:c.907del, ENST00000307000.7:c.892del, ENST00000549247.6:n.666del, ENST00000551114.2:n.569del, ENST00000553106.5:c.907del, ENST00000635477.1:n.68del, NM_000277.2(PAH):c.904delT (p.Ser303Profs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [MET], PP4 [MET] The c.904delT (p.Ser303Profs*38) variant in PAH has been observed in at least one patient with classic PKU (plasma phenylalanine greater than 1200 micromolar) with a known pathogenic variant p.Ser70del (PMID:16256386). This variant is absent in population databases including: 1000 Genomes, ESP, and extremely low in gnomAD. This is a single base pair deletion that creates a frameshift in exon 9 and is predicted to undergo nonsense mediated decay with the truncated region critical to protein function. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. 16256386, 16256386 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229840/MONDO:0009861/006 0.9941 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245470 102889 A G NM_000277.2(PAH):c.907T>C (p.Ser303Pro) 102889 CA229841 NM_000277.2:c.907T>C, NM_000277.1:c.907T>C, XM_011538422.1:c.907T>C, NM_001354304.1:c.907T>C, NM_000277.3:c.907T>C, ENST00000307000.7:c.892T>C, ENST00000549247.6:n.666T>C, ENST00000551114.2:n.569T>C, ENST00000553106.5:c.907T>C, ENST00000635477.1:n.68T>C, NC_000012.12:g.102851692A>G, CM000674.2:g.102851692A>G, NC_000012.11:g.103245470A>G, CM000674.1:g.103245470A>G, NC_000012.10:g.101769600A>G, NG_008690.1:g.70911T>C, NG_008690.2:g.111719T>C, NM_000277.2(PAH):c.907T>C (p.Ser303Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET] The c.907T>C (p.Ser303Pro) variant in PAH has been reported in 1 affected individual (BH4 deficiency excluded). (PP4_Moderate; PMID: 9634518). This variant is absent in population databases (PM2). This variant was detected with p.D282G (LP via PAH workgroup) (PM3; PMID: 16256386). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. 9634518, 16256386 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229841/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245465 102892 C T NM_000277.2(PAH):c.912G>A (p.Gln304=) 102892 CA229845 NM_000277.2:c.912G>A, NM_000277.1:c.912G>A, XM_011538422.1:c.912G>A, NM_001354304.1:c.912G>A, NM_000277.3:c.912G>A, ENST00000307000.7:c.897G>A, ENST00000549247.6:n.671G>A, ENST00000551114.2:n.574G>A, ENST00000553106.5:c.912G>A, ENST00000635477.1:n.73G>A, NC_000012.12:g.102851687C>T, CM000674.2:g.102851687C>T, NC_000012.11:g.103245465C>T, CM000674.1:g.103245465C>T, NC_000012.10:g.101769595C>T, NG_008690.1:g.70916G>A, NG_008690.2:g.111724G>A, NM_000277.2(PAH):c.912G>A (p.Gln304=) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET] The c.912G>A (p.Gln304Gln) variant in PAH has been reported in multiple PKU patients (BH4 deficiency excluded in some) (PMID: 23514811). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF=0.000004). This is a synonymous variant that occurs at the junction of exon8/intron8, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by reducing (~20%) the canonical donor site. p.Gln304= has been detected with multiple pathogenic variants without confirmation of parental testing to determine phase: R241H (VarID102804, PMID: 27413125); K363fsdelG (c.1089delG, VarID102518, PMID: 8659548); I65T (VarID636) and A300S (VarID92751, PMID: 2351481); p.R176L (VarID631, PMID: 23500595). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3_strong, PP4_moderate. 7766951, 23514811, 24941924, 23500595, 8659548, 26413448, 23514811, 27413125 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA229845/MONDO:0009861/006 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103240702 102905 G A NM_000277.2(PAH):c.940C>T (p.Pro314Ser) 102905 CA229865 NM_000277.2:c.940C>T, NC_000012.12:g.102846924G>A, CM000674.2:g.102846924G>A, NC_000012.11:g.103240702G>A, CM000674.1:g.103240702G>A, NC_000012.10:g.101764832G>A, NG_008690.1:g.75679C>T, NG_008690.2:g.116487C>T, NM_000277.1:c.940C>T, XM_011538422.1:c.913-2493C>T, NM_001354304.1:c.940C>T, NM_000277.3:c.940C>T, ENST00000307000.7:c.925C>T, ENST00000549247.6:n.699C>T, ENST00000551114.2:n.602C>T, ENST00000553106.5:c.940C>T, ENST00000635477.1:n.74-2493C>T, ENST00000635528.1:n.455C>T, NM_000277.2(PAH):c.940C>T (p.Pro314Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PM5 [MET], PP3 [Unmet], PS3 [MET] The c.940C>T (p.Pro314Ser) variant in PAH is absent in population databases, and is in the same codon as two previously described Pathogenic/Likely pathogenic variants (p.Pro314His and p.Pro314Thr). It has been found in trans with a pathogenic variant (p.R408W) in a patient with PAH deficiency (BH4 defects excluded, PMID: 12501224). Functional studies showed it has 26% enzyme activity compared to wild type controls. PMID: 18590700. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PM5. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229865/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103240679 102911 G A NM_000277.2(PAH):c.963C>T (p.Leu321=) 102911 CA229873 NM_000277.2:c.963C>T, NM_000277.1:c.963C>T, XM_011538422.1:c.913-2470C>T, NM_001354304.1:c.963C>T, NM_000277.3:c.963C>T, ENST00000307000.7:c.948C>T, ENST00000549247.6:n.722C>T, ENST00000551114.2:n.625C>T, ENST00000553106.5:c.963C>T, ENST00000635477.1:n.74-2470C>T, ENST00000635528.1:n.478C>T, NC_000012.12:g.102846901G>A, CM000674.2:g.102846901G>A, NC_000012.11:g.103240679G>A, CM000674.1:g.103240679G>A, NC_000012.10:g.101764809G>A, NG_008690.1:g.75702C>T, NG_008690.2:g.116510C>T, NM_000277.2(PAH):c.963C>T (p.Leu321=) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Benign BP7 [MET], BS1 [MET], BS2 [MET], BS3-Supporting [MET] PAH-specific ACMG/AMP criteria applied: BS1: >0.02% as set by the PAH specific specifications; BP7: ; BS3_Supporting: cDNA method demonstrates 98% and intinic system demonstrates 81% residual enzyme activity; BS2: 38 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BP7, BS3_Supporting, BS2). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-07-29 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA229873/MONDO:0009861/006 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 12 103237559 120258 T A NM_000277.2(PAH):c.1066-2A>T 120258 CA267625 NM_000277.2:c.1066-2A>T, NM_000277.1:c.1066-2A>T, XM_011538422.1:c.1009-2A>T, NM_001354304.1:c.1066-2A>T, NM_000277.3:c.1066-2A>T, ENST00000307000.7:c.1051-2A>T, ENST00000549247.6:n.825-2A>T, ENST00000551114.2:n.728-2A>T, ENST00000553106.5:c.1066-2A>T, ENST00000635477.1:n.170-2A>T, ENST00000635528.1:n.581-2A>T, NC_000012.12:g.102843781T>A, CM000674.2:g.102843781T>A, NC_000012.11:g.103237559T>A, CM000674.1:g.103237559T>A, NC_000012.10:g.101761689T>A, NG_008690.1:g.78822A>T, NG_008690.2:g.119630A>T, NM_000277.2(PAH):c.1066-2A>T PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PVS1 [MET] The c.1066-2A>T variant in PAH is absent from all population databases, and has been identified in a patient in which a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine. PMID: 21307867. It is a null variant where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 11 is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PVS1, PM2. 21307867 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA267625/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103237460 120260 A G NM_000277.2(PAH):c.1163T>C (p.Val388Ala) 120260 CA267628 NM_000277.2:c.1163T>C, NC_000012.12:g.102843682A>G, CM000674.2:g.102843682A>G, NC_000012.11:g.103237460A>G, CM000674.1:g.103237460A>G, NC_000012.10:g.101761590A>G, NG_008690.1:g.78921T>C, NG_008690.2:g.119729T>C, NM_000277.1:c.1163T>C, XM_011538422.1:c.1106T>C, NM_001354304.1:c.1163T>C, NM_000277.3:c.1163T>C, ENST00000307000.7:c.1148T>C, ENST00000549247.6:n.922T>C, ENST00000551114.2:n.825T>C, ENST00000553106.5:c.1163T>C, ENST00000635477.1:n.267T>C, ENST00000635528.1:n.678T>C, NM_000277.2(PAH):c.1163T>C (p.Val388Ala) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM5 [MET], PM3 [Unmet], PP3 [MET], PP4 [MET] The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The variant results in the substitution of a moderately conserved Valine residue with Alanine, a physiochemically similar amino acid. However, the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., Predicted deleterious in SIFT, Polyphen2, Mutation Taster. REVEL= 0.919) (PP3). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Other missense changes at this Valine residue (Val388) have been previously reported Pathogenic or Likely Pathogenic in ClinVar, e.g., p.Val388Met (Pathogenic per internal PAH ClinGen Working Group classification, ClinVar ID 619), as well as p.Val388Leu (PM5). The c.181A>G (p.Asn61Asp) variant in PAH has been reported in 1 individual with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 12501224). This variant is absent in population databases (PM2). This variant was detected with p.R261Q (Pathogenic/likely pathogenic in ClinVar) (PM3; PMID: 12501224). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM5, PP3. 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267628/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103234253 120265 A G NM_000277.2(PAH):c.1240T>C (p.Tyr414His) 120265 CA267637 NM_000277.2:c.1240T>C, NM_000277.1:c.1240T>C, XM_011538422.1:c.1183T>C, NM_001354304.1:c.1240T>C, NM_000277.3:c.1240T>C, ENST00000307000.7:c.1225T>C, ENST00000551114.2:n.902T>C, ENST00000553106.5:c.1240T>C, ENST00000635477.1:n.344T>C, ENST00000635528.1:n.755T>C, NC_000012.12:g.102840475A>G, CM000674.2:g.102840475A>G, NC_000012.11:g.103234253A>G, CM000674.1:g.103234253A>G, NC_000012.10:g.101758383A>G, NG_008690.1:g.82128T>C, NG_008690.2:g.122936T>C, NM_000277.2(PAH):c.1240T>C (p.Tyr414His) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [MET], PP3 [MET] The c.1240T>C (p.Tyr414His) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 125859); the collection method is stated as “literature only” and no further information is provided. To our knowledge, as of 4/29/19, it has not been reported in the published literature. The variant results in the substitution of a highly conserved Tyrosine residue with Histidine, a physiochemically distinct amino acid (nonpolar versus basic side chains), and the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., Predicted deleterious in SIFT, Polyphen2, Mutation Taster. REVEL= 0.969) (PP3). It is present at extremely low frequency in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00001, in the gnomAD/ExAC Non-Finnish European subpopulation, which falls below the 0.0002 allele frequency cutoff for PAH variants (PM2). Another missense variant at this site, p.Tyr414Cys, has been previously reported Pathogenic, including by the ClinGen PAH working group (see ClinVar variant ID 593) (PM5). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267637/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103306573 120266 A G NM_000277.2(PAH):c.164T>C (p.Phe55Ser) 120266 CA267639 NM_000277.2:c.164T>C, NM_000277.1:c.164T>C, XM_011538422.1:c.164T>C, NM_001354304.1:c.164T>C, XM_017019370.2:c.164T>C, NM_000277.3:c.164T>C, ENST00000307000.7:c.149T>C, ENST00000546844.1:c.164T>C, ENST00000548677.2:n.251T>C, ENST00000548928.1:n.86T>C, ENST00000549111.5:n.260T>C, ENST00000550978.6:n.148T>C, ENST00000551337.5:c.164T>C, ENST00000551988.5:n.253T>C, ENST00000553106.5:c.164T>C, ENST00000635500.1:n.132T>C, NC_000012.12:g.102912795A>G, CM000674.2:g.102912795A>G, NC_000012.11:g.103306573A>G, CM000674.1:g.103306573A>G, NC_000012.10:g.101830703A>G, NG_008690.1:g.9808T>C, NG_008690.2:g.50616T>C, NM_000277.2(PAH):c.164T>C (p.Phe55Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM5 [Unmet], PM3 [MET], PP3 [MET], PP4 [MET] The c.164T>C (p.Phe55Ser) variant in PAH is reported in 1 French patient with classic PKU. BH4 deficiency was not assessed. It was detected with a known pathogenic variant c.1066-11G>A (PMID: 26666653). This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.96. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4, PP3. 26666653, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA267639/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288669 120270 C A NM_000277.2(PAH):c.196G>T (p.Glu66Ter) 120270 CA267645 NM_000277.2:c.196G>T, NM_000277.1:c.196G>T, XM_011538422.1:c.196G>T, NM_001354304.1:c.196G>T, XM_017019370.2:c.196G>T, NM_000277.3:c.196G>T, ENST00000307000.7:c.181G>T, ENST00000546844.1:c.196G>T, ENST00000548677.2:n.283G>T, ENST00000548928.1:n.118G>T, ENST00000549111.5:n.292G>T, ENST00000550978.6:n.180G>T, ENST00000551337.5:c.196G>T, ENST00000551988.5:n.285G>T, ENST00000553106.5:c.196G>T, ENST00000635500.1:n.164G>T, NC_000012.12:g.102894891C>A, CM000674.2:g.102894891C>A, NC_000012.11:g.103288669C>A, CM000674.1:g.103288669C>A, NC_000012.10:g.101812799C>A, NG_008690.1:g.27712G>T, NG_008690.2:g.68520G>T, NM_000277.2(PAH):c.196G>T (p.Glu66Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET], PM3-Supporting [MET] The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported in one proband with classic PKU (PMID: 26666653) (PP4). The proband was heterozygous for the variant and also harbor the pathogenic allele (per ClinGen VCEP) c. 1315+1G>A; however, the phase of the variants was not confirmed via parental testing. (PM3_supporting). The sequence change results in a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting. 26666653, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267645/MONDO:0009861/006 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288653 120271 C CGAGAAG NM_000277.2(PAH):c.205_210dup (p.Ser70_Arg71insProSer) 120271 CA267647 NM_000277.2:c.205_210dup, NC_000012.12:g.102894877_102894882dup, CM000674.2:g.102894877_102894882dup, NC_000012.11:g.103288655_103288660dup, CM000674.1:g.103288655_103288660dup, NC_000012.10:g.101812785_101812790dup, NG_008690.1:g.27722_27727dup, NG_008690.2:g.68530_68535dup, NM_000277.1:c.206_211dup, XM_011538422.1:c.206_211dup, NM_000277.2:c.206_211dup, NM_001354304.1:c.206_211dup, XM_017019370.2:c.206_211dup, NM_000277.3:c.206_211dup, ENST00000307000.7:c.191_196dup, ENST00000546844.1:c.206_211dup, ENST00000548677.2:n.293_298dup, ENST00000548928.1:n.128_133dup, ENST00000549111.5:n.302_307dup, ENST00000550978.6:n.190_195dup, ENST00000551337.5:c.206_211dup, ENST00000551988.5:n.295_300dup, ENST00000553106.5:c.206_211dup, ENST00000635500.1:n.174_179dup, NM_000277.2(PAH):c.205_210dup (p.Ser70_Arg71insProSer) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM4 [MET] PAH-specific ACMG/AMP criteria applied: PM2: chr12-103288654--GAGAAG; Absent from population databases; PM4: in-frame insertion. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA267647/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288515 120273 G A NM_000277.2(PAH):c.350C>T (p.Thr117Ile) 120273 CA267651 NM_000277.2:c.350C>T, NC_000012.12:g.102894737G>A, CM000674.2:g.102894737G>A, NC_000012.11:g.103288515G>A, CM000674.1:g.103288515G>A, NC_000012.10:g.101812645G>A, NG_008690.1:g.27866C>T, NG_008690.2:g.68674C>T, NM_000277.1:c.350C>T, XM_011538422.1:c.350C>T, NM_001354304.1:c.350C>T, XM_017019370.2:c.350C>T, NM_000277.3:c.350C>T, ENST00000307000.7:c.335C>T, ENST00000546844.1:c.350C>T, ENST00000548928.1:n.272C>T, ENST00000549111.5:n.446C>T, ENST00000550978.6:n.334C>T, ENST00000551337.5:c.350C>T, ENST00000551988.5:n.439C>T, ENST00000553106.5:c.350C>T, NM_000277.2(PAH):c.350C>T (p.Thr117Ile) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [Unmet], PP3 [Unmet] PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC& gnomAD (MAF 0.00018). Absent from 1000G, ESP. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA267651/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103288514 120274 TG T NM_000277.2(PAH):c.350delC (p.Thr117Lysfs) 120274 CA267653 NM_000277.2:c.350delC, NM_000277.1:c.350del, XM_011538422.1:c.350del, NM_000277.2:c.350del, NM_001354304.1:c.350del, XM_017019370.2:c.350del, NM_000277.3:c.350del, ENST00000307000.7:c.335del, ENST00000546844.1:c.350del, ENST00000548928.1:n.272del, ENST00000549111.5:n.446del, ENST00000550978.6:n.334del, ENST00000551337.5:c.350del, ENST00000551988.5:n.439del, ENST00000553106.5:c.350del, NC_000012.12:g.102894737del, CM000674.2:g.102894737del, NC_000012.11:g.103288515del, CM000674.1:g.103288515del, NC_000012.10:g.101812645del, NG_008690.1:g.27866del, NG_008690.2:g.68674del, NM_000277.2(PAH):c.350delC (p.Thr117Lysfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic BS1 [Unmet], PM2 [MET], PVS1 [MET], PP4 [MET], BS2 [Unmet], BA1 [Unmet], PS3 [Unmet] The c.350delC variant in PAH has been previously reported in at least 2 Arab-Israeli probands with classic PKU (PMID: 18299955; PMID: 18294361); BH4 deficiency was not excluded (PP4). The variant is a frameshift variant occurring in exon 3 of 13 in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and the Greater Middle East Variome (PM2). 18294361, 18299955 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267653/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103271234 120275 A T NM_000277.2(PAH):c.441+6T>A 120275 CA267654 NM_000277.2:c.441+6T>A, NM_000277.1:c.441+6T>A, XM_011538422.1:c.441+6T>A, NM_001354304.1:c.441+6T>A, XM_017019370.2:c.441+6T>A, NM_000277.3:c.441+6T>A, ENST00000307000.7:c.426+6T>A, ENST00000549111.5:n.537+6T>A, ENST00000550978.6:n.431T>A, ENST00000551988.5:n.530+6T>A, ENST00000553106.5:c.441+6T>A, NC_000012.12:g.102877456A>T, CM000674.2:g.102877456A>T, NC_000012.11:g.103271234A>T, CM000674.1:g.103271234A>T, NC_000012.10:g.101795364A>T, NG_008690.1:g.45147T>A, NG_008690.2:g.85955T>A, NM_000277.2(PAH):c.441+6T>A PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [MET], PM3-Strong [MET] The c.441+6T>A variant in PAH has been reported in at least 2 patients with PKU (BH4 deficiency ruled out), who carried pathogenic variants (ClinVar IDs: 589 & 576) (PMID: 22526846). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF= 0.000004). This intronic variant changes a moderately conserved nucleotide, and computational analyses (Alamut) predict that this variant may weaken (~60%) the splice donor site of intron 4. Based on the available information, this variant is considered to be likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP3, PP4_M, PM2, PM3_S. 22526846, 22526846 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267654/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260379 120277 G T NM_000277.2(PAH):c.504C>A (p.Tyr168Ter) 120277 CA267656 NM_000277.2:c.504C>A, NM_000277.1:c.504C>A, XM_011538422.1:c.504C>A, NM_001354304.1:c.504C>A, XM_017019370.2:c.504C>A, NM_000277.3:c.504C>A, ENST00000307000.7:c.489C>A, ENST00000549111.5:n.600C>A, ENST00000551988.5:n.530+10861C>A, ENST00000553106.5:c.504C>A, NC_000012.12:g.102866601G>T, CM000674.2:g.102866601G>T, NC_000012.11:g.103260379G>T, CM000674.1:g.103260379G>T, NC_000012.10:g.101784509G>T, NG_008690.1:g.56002C>A, NG_008690.2:g.96810C>A, NM_000277.2(PAH):c.504C>A (p.Tyr168Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET], PM3-Supporting [MET] The c.504C>A (p.Tyr168Ter) variant in PAH has been previously reported in one proband with mild hyperphenylalanemia (PMID: 26666653; PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH VCEP, see ClinVar ID 92751) c.898G>T (p.Ala300Ser); however, the phase of the variants was not confirmed via parental testing (PM3_supporting).The sequence change results in a nonsense variant which occurs in exon 5 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting. 26666653, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267656/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249072 120278 TC AA NM_000277.2(PAH):c.547_548delGAinsTT (p.Glu183Leu) 120278 CA267658 NM_000277.2:c.547_548delGAinsTT, NC_000012.12:g.102855294_102855295delinsAA, CM000674.2:g.102855294_102855295delinsAA, NC_000012.11:g.103249072_103249073delinsAA, CM000674.1:g.103249072_103249073delinsAA, NC_000012.10:g.101773202_101773203delinsAA, NG_008690.1:g.67308_67309delinsTT, NG_008690.2:g.108116_108117delinsTT, NM_000277.1:c.547_548delinsTT, XM_011538422.1:c.547_548delinsTT, NM_000277.2:c.547_548delinsTT, NM_001354304.1:c.547_548delinsTT, XM_017019370.2:c.547_548delinsTT, NM_000277.3:c.547_548delinsTT, ENST00000307000.7:c.532_533delinsTT, ENST00000549111.5:n.643_644delinsTT, ENST00000551988.5:n.568_569delinsTT, ENST00000553106.5:c.547_548delinsTT, NM_000277.2(PAH):c.547_548delGAinsTT (p.Glu183Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM3 [MET], PP4 [MET], PP3 [MET] The c.547_548delGAinsTT PAH variant has been identified in at least one patient with classic PKU (PMID: 26666653). It was detected in trans with the pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608). This variant is absent from 1000G, ESP, and gnomAD databases. It is predicted deleterious in multiple in silico models. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. 26666653, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267658/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249052 120279 C T NM_000277.2(PAH):c.568G>A (p.Val190Met) 120279 CA267660 NM_000277.2:c.568G>A, NM_000277.1:c.568G>A, XM_011538422.1:c.568G>A, NM_001354304.1:c.568G>A, XM_017019370.2:c.568G>A, NM_000277.3:c.568G>A, ENST00000307000.7:c.553G>A, ENST00000549111.5:n.664G>A, ENST00000553106.5:c.568G>A, NC_000012.12:g.102855274C>T, CM000674.2:g.102855274C>T, NC_000012.11:g.103249052C>T, CM000674.1:g.103249052C>T, NC_000012.10:g.101773182C>T, NG_008690.1:g.67329G>A, NG_008690.2:g.108137G>A, NM_000277.2(PAH):c.568G>A (p.Val190Met) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [MET], PP3 [MET] The c.568G>A (p.Val190Met) variant in PAH has not been reported in the literature to our knowledge. The reference from BioPKU (Namour B, Jeannesson E, Chery C, Gueant JL, Feillet F, 2013) cannot be located. This variant is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.836. Another variant at this amino acid (p.V190G) is interpreted as pathogenic by the PAH VCEP. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA267660/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103249029 120280 C G NM_000277.2(PAH):c.591G>C (p.Leu197Phe) 120280 CA267662 NM_000277.2:c.591G>C, NC_000012.12:g.102855251C>G, CM000674.2:g.102855251C>G, NC_000012.11:g.103249029C>G, CM000674.1:g.103249029C>G, NC_000012.10:g.101773159C>G, NG_008690.1:g.67352G>C, NG_008690.2:g.108160G>C, NM_000277.1:c.591G>C, XM_011538422.1:c.591G>C, NM_001354304.1:c.591G>C, XM_017019370.2:c.591G>C, NM_000277.3:c.591G>C, ENST00000307000.7:c.576G>C, ENST00000549111.5:n.687G>C, ENST00000553106.5:c.591G>C, NM_000277.2(PAH):c.591G>C (p.Leu197Phe) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET] The c.591G>C (p.Leu197Phe) variant in PAH has been reported in 3 individuals with classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 18299955). This variant is absent in population databases (PM2). This variant was detected with a pathogenic variant (c.168+1G>A) and twice in the homozygous state (PM3). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen2, MutationTaster, REVEL=0.82). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. 18299955, 18299955 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267662/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246650 120285 A C NM_000277.2(PAH):c.785T>G (p.Val262Gly) 120285 CA267671 NM_000277.2:c.785T>G, NM_000277.1:c.785T>G, XM_011538422.1:c.785T>G, NM_001354304.1:c.785T>G, NM_000277.3:c.785T>G, ENST00000307000.7:c.770T>G, ENST00000549247.6:n.544T>G, ENST00000553106.5:c.785T>G, NC_000012.12:g.102852872A>C, CM000674.2:g.102852872A>C, NC_000012.11:g.103246650A>C, CM000674.1:g.103246650A>C, NC_000012.10:g.101770780A>C, NG_008690.1:g.69731T>G, NG_008690.2:g.110539T>G, NM_000277.2(PAH):c.785T>G (p.Val262Gly) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM5 [Unmet], PM3 [MET], PP3 [MET], PP4 [MET] The c.785T>G (p.Val262Gly) variant in PAH is observed in 1 patient with classic PKU. BH4 deficiencies were not assessed. It was detected with a known pathogenic variant p.F39L. PMID: 26666653. This variant is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen-2, MutationTaster, and REVEL=0.954. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4, PP3. 26666653, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA267671/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246639 120286 T G NM_000277.2(PAH):c.796A>C (p.Thr266Pro) 120286 CA267673 NM_000277.2:c.796A>C, NM_000277.1:c.796A>C, XM_011538422.1:c.796A>C, NM_001354304.1:c.796A>C, NM_000277.3:c.796A>C, ENST00000307000.7:c.781A>C, ENST00000549247.6:n.555A>C, ENST00000553106.5:c.796A>C, NC_000012.12:g.102852861T>G, CM000674.2:g.102852861T>G, NC_000012.11:g.103246639T>G, CM000674.1:g.103246639T>G, NC_000012.10:g.101770769T>G, NG_008690.1:g.69742A>C, NG_008690.2:g.110550A>C, NM_000277.2(PAH):c.796A>C (p.Thr266Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3 [MET], PP3 [MET] The c.796A>C (p.Thr266Pro) variant in PAH is reported in 1 classic PKU patient with BH4 deficiency excluded. (PMID: 26666653, 23430918) It was detected with p.V190A, which is interpreted as pathogenic by our PAH VCEP. (PMID: 23430918) This variant is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen-2, MutationTaster, and REVEL=0.98. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3. 26666653, 23430918, 23430918 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA267673/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246623 120287 T A NM_000277.2(PAH):c.812A>T (p.His271Leu) 120287 CA267675 NM_000277.2:c.812A>T, NM_000277.1:c.812A>T, XM_011538422.1:c.812A>T, NM_001354304.1:c.812A>T, NM_000277.3:c.812A>T, ENST00000307000.7:c.797A>T, ENST00000549247.6:n.571A>T, ENST00000553106.5:c.812A>T, NC_000012.12:g.102852845T>A, CM000674.2:g.102852845T>A, NC_000012.11:g.103246623T>A, CM000674.1:g.103246623T>A, NC_000012.10:g.101770753T>A, NG_008690.1:g.69758A>T, NG_008690.2:g.110566A>T, NM_000277.2(PAH):c.812A>T (p.His271Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.957; PP4_Moderate: H271L seen in a Chinese PKU patient. BH4 deficiencies excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:26503515). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate). 26503515 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA267675/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246597 120288 CG C NM_000277.2(PAH):c.837delC (p.Glu280Asnfs) 120288 CA267677 NM_000277.2:c.837del, NM_000277.1:c.837del, XM_011538422.1:c.837del, NM_001354304.1:c.837del, NM_000277.3:c.837del, ENST00000307000.7:c.822del, ENST00000549247.6:n.596del, ENST00000553106.5:c.837del, NC_000012.12:g.102852824del, CM000674.2:g.102852824del, NC_000012.11:g.103246602del, CM000674.1:g.103246602del, NC_000012.10:g.101770732del, NG_008690.1:g.69783del, NG_008690.2:g.110591del, NM_000277.2(PAH):c.837delC (p.Glu280Asnfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [MET], PP4 [MET] The c.837del frameshift variant has been identified in at least 2 probands with classic PKU, BH4 deficiency not excluded (PMIDs: 10598814, 26666653). It has been detected in trans with pathogenic variants V388M (PMID: 10598814) and c.1315+1G>A (PMID: 26666653). This variant is absent from 1000G, Exac, and gnomAD databases. C.837delC generates a frameshift predicted to result in a premature stop codon 61 residues downstream in exon 10 and undergo NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP4. 26666653, 10598814, 26666653, 10598814 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267677/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245490 120291 T C NM_000277.2(PAH):c.887A>G (p.Asp296Gly) 120291 CA267682 NM_000277.2:c.887A>G, NM_000277.1:c.887A>G, XM_011538422.1:c.887A>G, NM_001354304.1:c.887A>G, NM_000277.3:c.887A>G, ENST00000307000.7:c.872A>G, ENST00000549247.6:n.646A>G, ENST00000551114.2:n.549A>G, ENST00000553106.5:c.887A>G, ENST00000635477.1:n.48A>G, NC_000012.12:g.102851712T>C, CM000674.2:g.102851712T>C, NC_000012.11:g.103245490T>C, CM000674.1:g.103245490T>C, NC_000012.10:g.101769620T>C, NG_008690.1:g.70891A>G, NG_008690.2:g.111699A>G, NM_000277.2(PAH):c.887A>G (p.Asp296Gly) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [Unmet], PP4 [MET], PP3 [MET], PM3-Supporting [MET] The c.887A>G (p.Asp296Gly) variant in PAH has been reported in a proband with classic PKU (PMID: 26666653; PP4). The proband was heterozygous for variant; it was found with the known pathogenic (per ClinGen PAH Working Group – see ClinVar variant ID 577) c.1222C > T (p.Arg408Trp) allele; however, the although paper did say that parental samples were collected in the study, it did not explicitly state whether the phase of the variants was confirmed via parental testing. Thus, PM3 is downgraded to supporting. The variant is predicted damaging by multiple lines of computational evidence (PP3). It is absent from ethnically diverse control databases (PM2). Another missense at the site, p.Asp296His, has been previously reported (BioPKU PAH0955) heterozygous in a Chinese proband with PKU; no further information appears to be provided in the manuscript or supplementary information regarding phenotype or second variant (PMID: 26503515). . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_supporting, PP3. 26666653, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267682/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103240709 120297 CAG C NM_000277.2(PAH):c.931_932delCT (p.Leu311Glyfs) 120297 CA267689 NM_000277.2:c.931_932del, NC_000012.12:g.102846936_102846937del, CM000674.2:g.102846936_102846937del, NC_000012.11:g.103240714_103240715del, CM000674.1:g.103240714_103240715del, NC_000012.10:g.101764844_101764845del, NG_008690.1:g.75670_75671del, NG_008690.2:g.116478_116479del, NM_000277.1:c.931_932del, XM_011538422.1:c.913-2502_913-2501del, NM_001354304.1:c.931_932del, NM_000277.3:c.931_932del, ENST00000307000.7:c.916_917del, ENST00000549247.6:n.690_691del, ENST00000551114.2:n.593_594del, ENST00000553106.5:c.931_932del, ENST00000635477.1:n.74-2502_74-2501del, ENST00000635528.1:n.446_447del, NM_000277.2(PAH):c.931_932delCT (p.Leu311Glyfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET], PM3-Supporting [MET] The c.931_932del frameshift variant has been identified in at least 1 proband with mild PKU, BH4 deficiency not excluded (PMID: 26666653). It has been detected in trans with the pathogenic variant R241C (PMID: 26666653). This variant is absent from 1000G, Exac, and gnomAD databases. c.931_932delCT generates a frameshift predicted to result in a premature stop codon 4 residues downstream in exon 9 and undergo NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3_Supporting, PM2, PP4. 26666653, 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267689/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103306581 120310 CA C NM_000277.2(PAH):c.155delT (p.Leu52Cysfs) 120310 CA267691 NC_000012.12:g.102912805del, CM000674.2:g.102912805del, NC_000012.11:g.103306583del, CM000674.1:g.103306583del, NC_000012.10:g.101830713del, NG_008690.1:g.9799del, NG_008690.2:g.50607del, NM_000277.1:c.155del, XM_011538422.1:c.155del, NM_000277.2:c.155del, NM_001354304.1:c.155del, XM_017019370.2:c.155del, NM_000277.3:c.155del, ENST00000307000.7:c.140del, ENST00000546844.1:c.155del, ENST00000548677.2:n.242del, ENST00000548928.1:n.77del, ENST00000549111.5:n.251del, ENST00000550978.6:n.139del, ENST00000551337.5:c.155del, ENST00000551988.5:n.244del, ENST00000553106.5:c.155del, ENST00000635500.1:n.123del, NM_000277.2(PAH):c.155delT (p.Leu52Cysfs) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] The c.155delT (p.Leu52Cysfs) is a frameshift variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in 1 individual with PKU (BH4 deficiency not excluded), who carried a second nonsense variant in PAH (PP4; PMID: 26666653 ). This variant is absent from population databases (PM2). In summary, this variant meets our criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. 26666653 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267691/MONDO:0009861/006 0.9941 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103260378 125436 G A NM_000277.2(PAH):c.505C>T (p.Arg169Cys) 125436 CA267693 NM_000277.2:c.505C>T, NC_000012.12:g.102866600G>A, CM000674.2:g.102866600G>A, NC_000012.11:g.103260378G>A, CM000674.1:g.103260378G>A, NC_000012.10:g.101784508G>A, NG_008690.1:g.56003C>T, NG_008690.2:g.96811C>T, NM_000277.1:c.505C>T, XM_011538422.1:c.505C>T, NM_001354304.1:c.505C>T, XM_017019370.2:c.505C>T, NM_000277.3:c.505C>T, ENST00000307000.7:c.490C>T, ENST00000549111.5:n.601C>T, ENST00000551988.5:n.530+10862C>T, ENST00000553106.5:c.505C>T, NM_000277.2(PAH):c.505C>T (p.Arg169Cys) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PP3 [Unmet], PM3-Strong [MET] The c.505C>T (p.Arg169Cys) PAH variant has been identified in at least 3 compound heterozygous probands with mild HPA to classic PKU, with at least 1 proband excluding BH4 deficiency (PMIDs: 28771436, 30050108, 30747360). It has been detected in trans with pathogenic variants Arg243Gln (ClinVar 591), Arg408Gln (ClinVar 577), and c.208_210del (ClinVar 102632). This variant occurs and a very low frequency of 0.00001194 in gnomAD. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate. 30747360, 30050108, 28771436, 30050108 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA267693/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89622915 127667 T C NM_000314.6(PTEN):c.-1311T>C 127667 CA287476 NM_000314.6:c.-1311T>C, NC_000010.11:g.87863158T>C, CM000672.2:g.87863158T>C, NC_000010.10:g.89622915T>C, CM000672.1:g.89622915T>C, NC_000010.9:g.89612895T>C, NG_007466.2:g.4721T>C, LRG_311:g.4721T>C, NG_033079.1:g.5280A>G, NM_001126049.1:c.-671A>G, ENST00000371953.7:c.-1312T>C, ENST00000445946.3:c.-671A>G, NM_000314.6(PTEN):c.-1311T>C KLLN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Benign BA1 [MET] PTEN c.-1311T>C (NC_000010.10:g.89622915T>C) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.0142 (1.42%, 23/1618 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-06-02 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA287476/MONDO:0017623/003 0.0122 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89623492 127672 G A NM_000314.6(PTEN):c.-734G>A 127672 CA10602385 NM_000314.6:c.-734G>A, NC_000010.11:g.87863735G>A, CM000672.2:g.87863735G>A, NC_000010.10:g.89623492G>A, CM000672.1:g.89623492G>A, NC_000010.9:g.89613472G>A, NG_007466.2:g.5298G>A, LRG_311:g.5298G>A, NG_033079.1:g.4703C>T, NM_000314.5:c.-734G>A, NM_001304717.2:c.-215G>A, NM_001304718.1:c.-1439G>A, NM_000314.7:c.-734G>A, NM_001304717.5:c.-215G>A, NM_001304718.2:c.-1439G>A, ENST00000371953.7:c.-735G>A, ENST00000610634.1:c.-837G>A, NM_000314.6(PTEN):c.-734G>A PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP2 [Unmet], PP3 [Unmet], PP4 [Unmet], PP1 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP5 [Unmet], BP7 [Unmet] PTEN c.-734G>A (NC_000010.10:g.89623492G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10602385/MONDO:0017623/003 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89623428 127674 G C NM_000314.6(PTEN):c.-798G>C 127674 CA000581 NM_000314.6:c.-798G>C, NM_000314.5:c.-798G>C, NM_001304717.2:c.-279G>C, NM_001304718.1:c.-1503G>C, NM_000314.7:c.-798G>C, NM_001304717.5:c.-279G>C, NM_001304718.2:c.-1503G>C, ENST00000371953.7:c.-799G>C, ENST00000610634.1:c.-901G>C, NC_000010.11:g.87863671G>C, CM000672.2:g.87863671G>C, NC_000010.10:g.89623428G>C, CM000672.1:g.89623428G>C, NC_000010.9:g.89613408G>C, NG_007466.2:g.5234G>C, LRG_311:g.5234G>C, NG_033079.1:g.4767C>G, NM_000314.6(PTEN):c.-798G>C PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [Unmet] PTEN c.-798G>C (NC_000010.10:g.89623428G>C) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000581/MONDO:0017623/003 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89623251 127685 G C NM_000314.6(PTEN):c.-975G>C 127685 CA000654 NM_000314.6:c.-975G>C, NM_000314.5:c.-975G>C, NM_001304717.2:c.-456G>C, NM_001304718.1:c.-1680G>C, ENST00000371953.7:c.-976G>C, ENST00000610634.1:c.-1078G>C, NC_000010.11:g.87863494G>C, CM000672.2:g.87863494G>C, NC_000010.10:g.89623251G>C, CM000672.1:g.89623251G>C, NC_000010.9:g.89613231G>C, NG_007466.2:g.5057G>C, LRG_311:g.5057G>C, NG_033079.1:g.4944C>G, NM_000314.6(PTEN):c.-975G>C PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BP7 [Unmet], BP5 [MET], BS1 [MET], BS3 [Unmet], BS4 [Unmet] PTEN c.-975G>C (g.89623251G>C) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.006 (0.6%, 21/3466 alleles) in the European (Finnish) subpopulation and 0.002 (0.2%, 30/14,976) in the European (Non-Finnish) subpopulation of the gnomAD cohort. (PMID 27535533)BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributors SCV000187238.1, SCV000149489.5) 22171747, 22171747 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000654/MONDO:0017623/003 0.0122 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89725066 127687 CAGT C NM_000314.6(PTEN):c.1052_1054delTAG (p.Val351del) 127687 CA000271 NM_000314.6:c.1052_1054delTAG, NC_000010.11:g.87965312_87965314del, CM000672.2:g.87965312_87965314del, NC_000010.10:g.89725069_89725071del, CM000672.1:g.89725069_89725071del, NC_000010.9:g.89715049_89715051del, NG_007466.2:g.106874_106876del, LRG_311:g.106874_106876del, NM_000314.5:c.1052_1054del, NM_000314.6:c.1052_1054del, NM_001304717.2:c.1571_1573del, NM_001304718.1:c.461_463del, XM_006717926.2:c.1007_1009del, XM_011539982.1:c.956_958del, XR_945791.1:n.1622_1624del, NM_000314.7:c.1052_1054del, NM_001304717.5:c.1571_1573del, NM_001304718.2:c.461_463del, ENST00000371953.7:c.1052_1054del, NM_000314.6(PTEN):c.1052_1054delTAG (p.Val351del) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET] PTEN c.1052_1054delTAG (p.V351del) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-11-08 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000271/MONDO:0017623/003 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89624312 127692 A G NM_000314.6(PTEN):c.79+7A>G 127692 CA000580 NM_000314.6:c.79+7A>G, NM_000314.5:c.79+7A>G, NM_001304717.2:c.598+7A>G, NM_001304718.1:c.-627+7A>G, XM_006717926.2:c.79+7A>G, XM_011539981.1:c.79+7A>G, XR_945789.1:n.791+7A>G, XR_945790.1:n.791+7A>G, XR_945791.1:n.791+7A>G, NM_000314.7:c.79+7A>G, NM_001304717.5:c.598+7A>G, NM_001304718.2:c.-627+7A>G, ENST00000371953.7:c.79+7A>G, ENST00000462694.1:n.81+7A>G, ENST00000487939.1:n.100+7A>G, ENST00000610634.1:c.-24+7A>G, ENST00000618586.1:n.55A>G, NC_000010.11:g.87864555A>G, CM000672.2:g.87864555A>G, NC_000010.10:g.89624312A>G, CM000672.1:g.89624312A>G, NC_000010.9:g.89614292A>G, NG_007466.2:g.6117A>G, LRG_311:g.6117A>G, NG_033079.1:g.3883T>C, NM_000314.6(PTEN):c.79+7A>G PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP4 [Unmet], PP1 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PS4 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [MET], BS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.79+7A>G (IVS1+7A>G) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) 25669429, 21659347, 28677221, 28677221 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-07-25 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000580/MONDO:0017623/003 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89720763 127696 G A NM_000314.6(PTEN):c.914G>A (p.Ser305Asn) 127696 CA000632 NM_000314.6:c.914G>A, NM_000314.5:c.914G>A, NM_001304717.2:c.1433G>A, NM_001304718.1:c.323G>A, XM_006717926.2:c.869G>A, XM_011539981.1:c.914G>A, XM_011539982.1:c.818G>A, XR_945791.1:n.1484G>A, NM_000314.7:c.914G>A, NM_001304717.5:c.1433G>A, NM_001304718.2:c.323G>A, ENST00000371953.7:c.914G>A, ENST00000472832.2:n.341G>A, NC_000010.11:g.87961006G>A, CM000672.2:g.87961006G>A, NC_000010.10:g.89720763G>A, CM000672.1:g.89720763G>A, NC_000010.9:g.89710743G>A, NG_007466.2:g.102568G>A, LRG_311:g.102568G>A, NM_000314.6(PTEN):c.914G>A (p.Ser305Asn) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], BS2 [Unmet], BS3-Supporting [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.914G>A (p.S305N) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000632/MONDO:0017623/003 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 16 68847240 127906 G A NM_004360.4(CDH1):c.1162G>A (p.Glu388Lys) 127906 CA157986 NM_004360.4:c.1162G>A, NM_004360.3:c.1162G>A, LRG_301t1:c.1162G>A, XM_011523488.1:c.427G>A, XM_011523489.1:c.427G>A, NM_001317184.1:c.1137+1074G>A, NM_001317185.1:c.-454G>A, NM_001317186.1:c.-658G>A, ENST00000261769.9:c.1162G>A, ENST00000422392.6:c.1137+1074G>A, ENST00000562836.5:n.1233G>A, ENST00000565810.1:n.206G>A, ENST00000566510.5:c.1006G>A, ENST00000566612.5:c.1162G>A, ENST00000611625.4:c.1162G>A, ENST00000612417.4:c.1162G>A, ENST00000621016.4:c.1162G>A, NC_000016.10:g.68813337G>A, CM000678.2:g.68813337G>A, NC_000016.9:g.68847240G>A, CM000678.1:g.68847240G>A, NC_000016.8:g.67404741G>A, NG_008021.1:g.81046G>A, LRG_301:g.81046G>A, NM_004360.4(CDH1):c.1162G>A (p.Glu388Lys) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], PP3 [Unmet], PP1 [Unmet], BP2-Strong [MET], BS2 [MET], PM4 [Unmet], BP4 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.1162G>A (p.Glu388Lys) variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; SCV000254804.3). The variant has also been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BP2_Strong, BS2. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA157986/MONDO:0007648/007 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 0, 0] 1 Uncertain Significance 16 68847375 127910 G A NM_004360.4(CDH1):c.1297G>A (p.Asp433Asn) 127910 CA288028 NM_004360.4:c.1297G>A, NM_004360.3:c.1297G>A, LRG_301t1:c.1297G>A, XM_011523488.1:c.562G>A, XM_011523489.1:c.562G>A, NM_001317184.1:c.1137+1209G>A, NM_001317185.1:c.-319G>A, NM_001317186.1:c.-523G>A, ENST00000261769.9:c.1297G>A, ENST00000422392.6:c.1137+1209G>A, ENST00000562836.5:n.1368G>A, ENST00000566510.5:c.1141G>A, ENST00000566612.5:c.1297G>A, ENST00000611625.4:c.1297G>A, ENST00000612417.4:c.1297G>A, ENST00000621016.4:c.1297G>A, NC_000016.10:g.68813472G>A, CM000678.2:g.68813472G>A, NC_000016.9:g.68847375G>A, CM000678.1:g.68847375G>A, NC_000016.8:g.67404876G>A, NG_008021.1:g.81181G>A, LRG_301:g.81181G>A, NM_004360.4(CDH1):c.1297G>A (p.Asp433Asn) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Uncertain Significance BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], PP3 [Unmet], PP1 [Unmet], BS2 [MET], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet] The c.1297G>A (p.Asp433Asn) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA288028/MONDO:0007648/007 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 16 68849506 127913 C T NM_004360.4(CDH1):c.1409C>T (p.Thr470Ile) 127913 CA151518 NM_004360.4:c.1409C>T, NM_004360.3:c.1409C>T, LRG_301t1:c.1409C>T, XM_011523488.1:c.674C>T, XM_011523489.1:c.674C>T, NM_001317184.1:c.1226C>T, NM_001317185.1:c.-140C>T, NM_001317186.1:c.-411C>T, ENST00000261769.9:c.1409C>T, ENST00000422392.6:c.1226C>T, ENST00000562836.5:n.1480C>T, ENST00000566510.5:c.*75C>T, ENST00000566612.5:c.1409C>T, ENST00000611625.4:c.1472C>T, ENST00000612417.4:c.1409C>T, ENST00000621016.4:c.1409C>T, NC_000016.10:g.68815603C>T, CM000678.2:g.68815603C>T, NC_000016.9:g.68849506C>T, CM000678.1:g.68849506C>T, NC_000016.8:g.67407007C>T, NG_008021.1:g.83312C>T, LRG_301:g.83312C>T, NM_004360.4(CDH1):c.1409C>T (p.Thr470Ile) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], PP3 [Unmet], PP1 [Unmet], BP2-Strong [MET], BS2 [MET], PM4 [Unmet], BP4 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.1409C>T (p.Thr470Ile) variant was observed in trans with a known pathogenic CDH1 variant with phase confirmed (BP2_Strong; PMID: 9537325). This variant was observed in the homozygous state in at least 6 individuals without a personal and/or family history of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer (BP2_Strong; internal laboratory contributors). Additionally, this variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BP2_Strong, BS2. 9537325 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA151518/MONDO:0007648/007 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 3 Uncertain Significance 16 68835597 127919 G A NM_004360.4(CDH1):c.188G>A (p.Arg63Gln) 127919 CA288048 NM_004360.4:c.188G>A, NM_004360.3:c.188G>A, LRG_301t1:c.188G>A, XM_011523488.1:c.-548G>A, XM_011523489.1:c.-548G>A, NM_001317184.1:c.188G>A, NM_001317185.1:c.-1428G>A, NM_001317186.1:c.-1632G>A, ENST00000261769.9:c.188G>A, ENST00000422392.6:c.188G>A, ENST00000562836.5:n.259G>A, ENST00000564676.5:n.470G>A, ENST00000564745.1:n.183G>A, ENST00000566510.5:c.188G>A, ENST00000566612.5:c.188G>A, ENST00000611625.4:c.188G>A, ENST00000612417.4:c.188G>A, ENST00000621016.4:c.188G>A, NC_000016.10:g.68801694G>A, CM000678.2:g.68801694G>A, NC_000016.9:g.68835597G>A, CM000678.1:g.68835597G>A, NC_000016.8:g.67393098G>A, NG_008021.1:g.69403G>A, LRG_301:g.69403G>A, NM_004360.4(CDH1):c.188G>A (p.Arg63Gln) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BP5 [Unmet], BP7 [Unmet], BS1 [MET], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [MET], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.188G>A (p.Arg63Gln) variant has an allele frequency of 0.00109 (0.11%, 6/5486 alleles) in the “Other” subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA288048/MONDO:0007648/007 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 16 68863674 127925 G A NM_004360.4(CDH1):c.2413G>A (p.Asp805Asn) 127925 CA157966 NM_004360.4:c.2413G>A, NM_004360.3:c.2413G>A, LRG_301t1:c.2413G>A, XM_011523488.1:c.1678G>A, XM_011523489.1:c.1678G>A, NM_001317184.1:c.2230G>A, NM_001317185.1:c.865G>A, NM_001317186.1:c.448G>A, ENST00000261769.9:c.2413G>A, ENST00000422392.6:c.2230G>A, ENST00000562118.1:n.631G>A, ENST00000562836.5:n.2484G>A, ENST00000566510.5:c.*1079G>A, ENST00000566612.5:c.*653G>A, ENST00000611625.4:c.2476G>A, ENST00000612417.4:c.1853+3217G>A, ENST00000621016.4:c.1866-4432G>A, NC_000016.10:g.68829771G>A, CM000678.2:g.68829771G>A, NC_000016.9:g.68863674G>A, CM000678.1:g.68863674G>A, NC_000016.8:g.67421175G>A, NG_008021.1:g.97480G>A, LRG_301:g.97480G>A, NM_004360.4(CDH1):c.2413G>A (p.Asp805Asn) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [MET], PS3 [Unmet], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.2413G>A (p.Asp805Asn) variant has an allele frequency of 0.00207 (0.21%, 21/10,148 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1. 24728327, 25980754, 23197654 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA157966/MONDO:0007648/007 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 16 68842734 127932 C T NM_004360.4(CDH1):c.670C>T (p.Arg224Cys) 127932 CA288074 NM_004360.4:c.670C>T, NM_004360.3:c.670C>T, LRG_301t1:c.670C>T, XM_011523488.1:c.-66C>T, XM_011523489.1:c.-66C>T, NM_001317184.1:c.670C>T, NM_001317185.1:c.-946C>T, NM_001317186.1:c.-1150C>T, ENST00000261769.9:c.670C>T, ENST00000422392.6:c.670C>T, ENST00000561751.1:n.437C>T, ENST00000562836.5:n.741C>T, ENST00000564676.5:n.952C>T, ENST00000566510.5:c.531+264C>T, ENST00000566612.5:c.670C>T, ENST00000567320.1:n.180C>T, ENST00000611625.4:c.670C>T, ENST00000612417.4:c.670C>T, ENST00000621016.4:c.670C>T, NC_000016.10:g.68808831C>T, CM000678.2:g.68808831C>T, NC_000016.9:g.68842734C>T, CM000678.1:g.68842734C>T, NC_000016.8:g.67400235C>T, NG_008021.1:g.76540C>T, LRG_301:g.76540C>T, NM_004360.4(CDH1):c.670C>T (p.Arg224Cys) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Uncertain Significance BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [MET], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.670C>T (p.Arg224Cys) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. 27582386 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA288074/MONDO:0007648/007 0.3246 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 0, 0] 3 Uncertain Significance 12 103246654 133314 G C NM_000277.2(PAH):c.781C>G (p.Arg261Gly) 133314 CA269921 NM_000277.2:c.781C>G, NC_000012.12:g.102852876G>C, CM000674.2:g.102852876G>C, NC_000012.11:g.103246654G>C, CM000674.1:g.103246654G>C, NC_000012.10:g.101770784G>C, NG_008690.1:g.69727C>G, NG_008690.2:g.110535C>G, NM_000277.1:c.781C>G, XM_011538422.1:c.781C>G, NM_001354304.1:c.781C>G, NM_000277.3:c.781C>G, ENST00000307000.7:c.766C>G, ENST00000549247.6:n.540C>G, ENST00000553106.5:c.781C>G, NM_000277.2(PAH):c.781C>G (p.Arg261Gly) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP3 [MET] The c.781C>G (p.Arg261Gly) variant in PAH has not been reported in the literature (to our knowledge). This variant is at extremely low frequency in gnomAD (MAF=0.00006, PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.962. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA269921/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68856080 133846 C G NM_004360.4(CDH1):c.1888C>G (p.Leu630Val) 133846 CA157951 NM_004360.4:c.1888C>G, NC_000016.10:g.68822177C>G, CM000678.2:g.68822177C>G, NC_000016.9:g.68856080C>G, CM000678.1:g.68856080C>G, NC_000016.8:g.67413581C>G, NG_008021.1:g.89886C>G, LRG_301:g.89886C>G, NM_004360.3:c.1888C>G, LRG_301t1:c.1888C>G, XM_011523488.1:c.1153C>G, XM_011523489.1:c.1153C>G, NM_001317184.1:c.1705C>G, NM_001317185.1:c.340C>G, NM_001317186.1:c.-78C>G, ENST00000261769.9:c.1888C>G, ENST00000422392.6:c.1705C>G, ENST00000562836.5:n.1959C>G, ENST00000566510.5:c.*554C>G, ENST00000566612.5:c.*128C>G, ENST00000611625.4:c.1951C>G, ENST00000612417.4:c.1830+58C>G, ENST00000621016.4:c.1865+23C>G, NM_004360.4(CDH1):c.1888C>G (p.Leu630Val) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [MET], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.1888C>G (p.Leu630Val) variant has an allele frequency of 0.00519 (0.52%, 98/18,866 alleles) in the East Asian subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA157951/MONDO:0007648/007 0.1877 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 3 Uncertain Significance 16 68842668 133853 G A NM_004360.4(CDH1):c.604G>A (p.Val202Ile) 133853 CA163776 NM_004360.4:c.604G>A, NM_004360.3:c.604G>A, LRG_301t1:c.604G>A, XM_011523488.1:c.-132G>A, XM_011523489.1:c.-132G>A, NM_001317184.1:c.604G>A, NM_001317185.1:c.-1012G>A, NM_001317186.1:c.-1216G>A, ENST00000261769.9:c.604G>A, ENST00000422392.6:c.604G>A, ENST00000561751.1:n.371G>A, ENST00000562836.5:n.675G>A, ENST00000564676.5:n.886G>A, ENST00000566510.5:c.531+198G>A, ENST00000566612.5:c.604G>A, ENST00000567320.1:n.114G>A, ENST00000611625.4:c.604G>A, ENST00000612417.4:c.604G>A, ENST00000621016.4:c.604G>A, NC_000016.10:g.68808765G>A, CM000678.2:g.68808765G>A, NC_000016.9:g.68842668G>A, CM000678.1:g.68842668G>A, NC_000016.8:g.67400169G>A, NG_008021.1:g.76474G>A, LRG_301:g.76474G>A, NM_004360.4(CDH1):c.604G>A (p.Val202Ile) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], PP3 [Unmet], PP1 [Unmet], BS2 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [MET], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.604G>A (p.Val202Ile) variant has an allele frequency of 0.00354 (0.35%, 109/30,772 alleles) in the South Asian subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA163776/MONDO:0007648/007 0.4999 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 0, 0] 1 Uncertain Significance 16 68847303 133855 T C NM_004360.4(CDH1):c.1225T>C (p.Trp409Arg) 133855 CA157989 NM_004360.4:c.1225T>C, NM_004360.3:c.1225T>C, LRG_301t1:c.1225T>C, XM_011523488.1:c.490T>C, XM_011523489.1:c.490T>C, NM_001317184.1:c.1137+1137T>C, NM_001317185.1:c.-391T>C, NM_001317186.1:c.-595T>C, ENST00000261769.9:c.1225T>C, ENST00000422392.6:c.1137+1137T>C, ENST00000562836.5:n.1296T>C, ENST00000565810.1:n.269T>C, ENST00000566510.5:c.1069T>C, ENST00000566612.5:c.1225T>C, ENST00000611625.4:c.1225T>C, ENST00000612417.4:c.1225T>C, ENST00000621016.4:c.1225T>C, NC_000016.10:g.68813400T>C, CM000678.2:g.68813400T>C, NC_000016.9:g.68847303T>C, CM000678.1:g.68847303T>C, NC_000016.8:g.67404804T>C, NG_008021.1:g.81109T>C, LRG_301:g.81109T>C, NM_004360.4(CDH1):c.1225T>C (p.Trp409Arg) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Uncertain Significance BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], PP3 [Unmet], PP1 [Unmet], BS2 [MET], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.1225T>C (p. Trp409Arg) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA157989/MONDO:0007648/007 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 112884118 135112 A G NM_002834.4(PTPN11):c.53A>G (p.Asn18Ser) 135112 CA161776 NM_002834.4:c.53A>G, NC_000012.12:g.112446314A>G, CM000674.2:g.112446314A>G, NC_000012.11:g.112884118A>G, CM000674.1:g.112884118A>G, NC_000012.10:g.111368501A>G, NG_007459.1:g.32583A>G, LRG_614:g.32583A>G, NM_002834.3:c.53A>G, LRG_614t1:c.53A>G, NM_080601.1:c.53A>G, XM_006719526.1:c.53A>G, XM_006719527.1:c.53A>G, XM_011538613.1:c.53A>G, NM_001330437.1:c.53A>G, NM_080601.2:c.53A>G, XM_011538613.2:c.53A>G, XM_017019722.1:c.53A>G, ENST00000351677.6:c.53A>G, ENST00000392597.5:c.53A>G, ENST00000635625.1:n.53A>G, NM_002834.4(PTPN11):c.53A>G (p.Asn18Ser) PTPN11 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.53A>G (p.Asn18Ser) variant in the PTPN11 gene is 0.056% (15/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA161776/MONDO:0021060/004 0.025 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 16 68845757 136055 C T NM_004360.4(CDH1):c.1003C>T (p.Arg335Ter) 136055 CA166866 NM_004360.4:c.1003C>T, NM_004360.3:c.1003C>T, LRG_301t1:c.1003C>T, XM_011523488.1:c.268C>T, XM_011523489.1:c.268C>T, NM_001317184.1:c.1003C>T, NM_001317185.1:c.-613C>T, NM_001317186.1:c.-817C>T, ENST00000261769.9:c.1003C>T, ENST00000422392.6:c.1003C>T, ENST00000561751.1:n.625C>T, ENST00000562836.5:n.1074C>T, ENST00000566510.5:c.847C>T, ENST00000566612.5:c.1003C>T, ENST00000611625.4:c.1003C>T, ENST00000612417.4:c.1003C>T, ENST00000621016.4:c.1003C>T, NC_000016.10:g.68811854C>T, CM000678.2:g.68811854C>T, NC_000016.9:g.68845757C>T, CM000678.1:g.68845757C>T, NC_000016.8:g.67403258C>T, NG_008021.1:g.79563C>T, LRG_301:g.79563C>T, NM_004360.4(CDH1):c.1003C>T (p.Arg335Ter) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [MET], PM2 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PM4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PP1-Strong [MET] The c.1003C>T (p.Arg335*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 16061854, 22723466, 17522512). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1, PP1_Strong. 16061854, 17522512, 22723466, 16061854, 17522512, 22723466 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA166866/MONDO:0007648/007 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 25398229 138061 G A NM_004985.4(KRAS):c.90C>T (p.Asp30=) 138061 CA291858 NM_004985.4:c.90C>T, NM_033360.3:c.90C>T, XM_006719069.2:c.90C>T, XM_011520653.1:c.90C>T, XM_006719069.4:c.90C>T, XM_011520653.3:c.90C>T, ENST00000256078.8:c.90C>T, ENST00000311936.7:c.90C>T, ENST00000556131.1:c.90C>T, ENST00000557334.5:c.90C>T, NC_000012.12:g.25245295G>A, CM000674.2:g.25245295G>A, NC_000012.11:g.25398229G>A, CM000674.1:g.25398229G>A, NC_000012.10:g.25289496G>A, NG_007524.1:g.10626C>T, NM_004985.4(KRAS):c.90C>T (p.Asp30=) KRAS RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.90C>T (p.Asp30=) variant in the KRAS gene is 0.0292% (5/6746) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA291858/MONDO:0021060/004 0.0122 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 19 4101261 138158 C T NM_030662.3(MAP2K2):c.546G>A (p.Ala182=) 138158 CA291993 NM_030662.3:c.546G>A, LRG_750t1:c.546G>A, XM_006722799.2:c.546G>A, XM_011528133.1:c.-25G>A, XM_017026989.1:c.546G>A, XM_017026990.1:c.546G>A, XM_017026991.1:c.546G>A, ENST00000262948.9:c.546G>A, ENST00000394867.8:c.255G>A, ENST00000593364.5:n.493G>A, ENST00000597008.5:n.147G>A, ENST00000597263.5:n.10G>A, ENST00000599345.1:n.816G>A, ENST00000601786.5:n.847G>A, ENST00000602167.5:n.266G>A, NC_000019.10:g.4101263C>T, CM000681.2:g.4101263C>T, NC_000019.9:g.4101261C>T, CM000681.1:g.4101261C>T, NC_000019.8:g.4052261C>T, NG_007996.1:g.27866G>A, LRG_750:g.27866G>A, NM_030662.3(MAP2K2):c.546G>A (p.Ala182=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.546G>A (p.Ala182=) variant in the MAP2K2 gene is 0.083% (7/3952) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA291993/MONDO:0021060/004 0.0003 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 19 4101032 138159 C T NM_030662.3(MAP2K2):c.690G>A (p.Thr230=) 138159 CA291996 NM_030662.3:c.690G>A, LRG_750t1:c.690G>A, XM_006722799.2:c.690G>A, XM_011528133.1:c.120G>A, XM_017026989.1:c.690G>A, XM_017026990.1:c.690G>A, XM_017026991.1:c.690G>A, ENST00000262948.9:c.690G>A, ENST00000394867.8:c.399G>A, ENST00000593364.5:n.637G>A, ENST00000597008.5:n.291G>A, ENST00000597263.5:n.154G>A, ENST00000599021.1:n.14G>A, ENST00000601786.5:n.991G>A, ENST00000602167.5:n.410G>A, NC_000019.10:g.4101034C>T, CM000681.2:g.4101034C>T, NC_000019.9:g.4101032C>T, CM000681.1:g.4101032C>T, NC_000019.8:g.4052032C>T, NG_007996.1:g.28095G>A, LRG_750:g.28095G>A, NM_030662.3(MAP2K2):c.690G>A (p.Thr230=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.690G>A (p.Thr230=) variant in the MAP2K2 gene is 0.1273% for Latino chromosomes by the Exome Aggregation Consortium (3/642 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). None https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2018-11-15 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA291996/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 19 4099293 138161 C T NM_030662.3(MAP2K2):c.825G>A (p.Leu275=) 138161 CA291999 NM_030662.3:c.825G>A, NC_000019.10:g.4099295C>T, CM000681.2:g.4099295C>T, NC_000019.9:g.4099293C>T, CM000681.1:g.4099293C>T, NC_000019.8:g.4050293C>T, NG_007996.1:g.29834G>A, LRG_750:g.29834G>A, LRG_750t1:c.825G>A, XM_006722799.2:c.705+1724G>A, XM_011528133.1:c.255G>A, XM_017026989.1:c.825G>A, XM_017026990.1:c.705+1724G>A, ENST00000262948.9:c.825G>A, ENST00000394867.8:c.534G>A, ENST00000593364.5:n.772G>A, ENST00000595715.1:n.640G>A, ENST00000597263.5:n.169+1724G>A, ENST00000599021.1:n.29+1724G>A, ENST00000600584.5:n.1385G>A, ENST00000601786.5:n.1126G>A, NM_030662.3(MAP2K2):c.825G>A (p.Leu275=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.825G>A (p.Leu275=) variant in the MAP2K2 gene is 0.142% (14/5968) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA291999/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 89725121 138835 T C NM_000314.6(PTEN):c.1104T>C (p.Asp368=) 138835 CA000293 NM_000314.6:c.1104T>C, NM_000314.5:c.1104T>C, NM_001304717.2:c.1623T>C, NM_001304718.1:c.513T>C, XM_006717926.2:c.1059T>C, XM_011539982.1:c.1008T>C, XR_945791.1:n.1674T>C, NM_000314.7:c.1104T>C, NM_001304717.5:c.1623T>C, NM_001304718.2:c.513T>C, ENST00000371953.7:c.1104T>C, NC_000010.11:g.87965364T>C, CM000672.2:g.87965364T>C, NC_000010.10:g.89725121T>C, CM000672.1:g.89725121T>C, NC_000010.9:g.89715101T>C, NG_007466.2:g.106926T>C, LRG_311:g.106926T>C, NM_000314.6(PTEN):c.1104T>C (p.Asp368=) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign BP4 [MET], BS1 [MET], BP7 [MET] PTEN c.1104T>C (p.D368=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0057 (0.57%, 130/22,966 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533)BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000293/MONDO:0017623/003 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 89623200 138836 C A NM_000314.6(PTEN):c.-1026C>A 138836 CA000105 NM_000314.6:c.-1026C>A, NM_000314.5:c.-1026C>A, NM_001304717.2:c.-507C>A, NM_001304718.1:c.-1731C>A, ENST00000371953.7:c.-1027C>A, ENST00000610634.1:c.-1129C>A, NC_000010.11:g.87863443C>A, CM000672.2:g.87863443C>A, NC_000010.10:g.89623200C>A, CM000672.1:g.89623200C>A, NC_000010.9:g.89613180C>A, NG_007466.2:g.5006C>A, LRG_311:g.5006C>A, NG_033079.1:g.4995G>T, NM_000314.6(PTEN):c.-1026C>A PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign BS1 [MET], BS2-Supporting [MET], BP5 [MET] PTEN c.-1026C>A (NC_000010.10:g.89623200C>A) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0056 (0.56%, 173/30,898 alleles) in the gnomAD cohort. (PMID 27535533)BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (Internal laboratory contributor(s) SCV000171228.5)BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributor(s) SCV000171228.5) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-11-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000105/MONDO:0017623/003 0.0059 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89623323 138837 G A NM_000314.6(PTEN):c.-903G>A 138837 CA000628 NM_000314.6:c.-903G>A, NM_000314.5:c.-903G>A, NM_001304717.2:c.-384G>A, NM_001304718.1:c.-1608G>A, ENST00000371953.7:c.-904G>A, ENST00000610634.1:c.-1006G>A, NC_000010.11:g.87863566G>A, CM000672.2:g.87863566G>A, NC_000010.10:g.89623323G>A, CM000672.1:g.89623323G>A, NC_000010.9:g.89613303G>A, NG_007466.2:g.5129G>A, LRG_311:g.5129G>A, NG_033079.1:g.4872C>T, NM_000314.6(PTEN):c.-903G>A PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Benign BA1 [MET] PTEN c.-903G>A (NC_000010.10:g.89623323G>A) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.011 (1.1%, 343/30,808 alleles) in the gnomAD cohort. (PMID 27535533) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000628/MONDO:0017623/003 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 12 112939998 138843 G A NM_002834.4(PTPN11):c.1650G>A (p.Ala550=) 138843 CA292973 NM_002834.4:c.1650G>A, NC_000012.12:g.112502194G>A, CM000674.2:g.112502194G>A, NC_000012.11:g.112939998G>A, CM000674.1:g.112939998G>A, NC_000012.10:g.111424381G>A, NG_007459.1:g.88463G>A, LRG_614:g.88463G>A, NM_002834.3:c.1650G>A, LRG_614t1:c.1650G>A, XM_006719526.1:c.1662G>A, XM_006719527.1:c.1548G>A, XM_011538613.1:c.1659G>A, NM_001330437.1:c.1662G>A, XM_011538613.2:c.1659G>A, XM_017019722.1:c.1647G>A, ENST00000351677.6:c.1650G>A, ENST00000635625.1:n.1662G>A, NM_002834.4(PTPN11):c.1650G>A (p.Ala550=) PTPN11 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1650G>A (p.Ala550=) variant in the PTPN11 gene is 0.067% (13/11548) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA292973/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 112724573 139104 C T NM_007373.3(SHOC2):c.457C>T (p.Leu153=) 139104 CA333154 NM_007373.3:c.457C>T, NC_000010.11:g.110964815C>T, CM000672.2:g.110964815C>T, NC_000010.10:g.112724573C>T, CM000672.1:g.112724573C>T, NC_000010.9:g.112714563C>T, NG_028922.1:g.50273C>T, LRG_753:g.50273C>T, NM_001269039.1:c.457C>T, LRG_753t1:c.457C>T, XM_011540216.1:c.-380-20813C>T, NM_001269039.2:c.457C>T, NM_001324336.1:c.457C>T, NM_001324337.1:c.457C>T, NR_136749.1:n.116-20813C>T, ENST00000265277.9:c.457C>T, ENST00000369452.8:c.457C>T, ENST00000489390.1:n.56-35600C>T, NM_007373.3(SHOC2):c.457C>T (p.Leu153=) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.457C>T (p.Leu153=) variant in the SHOC2 gene is 1.574% (1104/66696) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA333154/MONDO:0021060/004 0.0003 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 112769023 139108 C T NM_007373.3(SHOC2):c.1302C>T (p.Asn434=) 139108 CA293482 NM_007373.3:c.1302C>T, NC_000010.11:g.111009265C>T, CM000672.2:g.111009265C>T, NC_000010.10:g.112769023C>T, CM000672.1:g.112769023C>T, NC_000010.9:g.112759013C>T, NG_028922.1:g.94723C>T, LRG_753:g.94723C>T, NM_001269039.1:c.1164C>T, LRG_753t1:c.1302C>T, XM_011540216.1:c.219C>T, NM_001269039.2:c.1164C>T, NM_001324336.1:c.1302C>T, NM_001324337.1:c.1302C>T, NR_136749.1:n.714C>T, ENST00000265277.9:c.1164C>T, ENST00000369452.8:c.1302C>T, ENST00000451838.1:n.672C>T, ENST00000489390.1:n.516C>T, NM_007373.3(SHOC2):c.1302C>T (p.Asn434=) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BP7 [MET], BP5 [MET], BA1 [MET], BP2 [Unmet], BP4 [MET] The c.1302C>T (p.Asn434=) variant in the SHOC2 gene has been identified in a patient with an alternate molecular basis for disease (BP5; ClinVar SCV000171633.12). The silent p.Asn434= variant is not predicted by MaxEntScan to impact splicing (BP7, BP4).The filtering allele frequency of the c.1302C>T (p.Asn434=) variant is 0.74% for African chromosomes by the Exome Aggregation Consortium (87/9772 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5, BP4, BP7. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA293482/MONDO:0021060/004 0.0003 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 112771421 139110 A G NM_007373.3(SHOC2):c.1594A>G (p.Ser532Gly) 139110 CA293486 NM_007373.3:c.1594A>G, NM_001269039.1:c.1456A>G, LRG_753t1:c.1594A>G, XM_011540216.1:c.511A>G, NM_001269039.2:c.1456A>G, NM_001324336.1:c.1594A>G, NM_001324337.1:c.1594A>G, NR_136749.1:n.1006A>G, ENST00000265277.9:c.1456A>G, ENST00000369452.8:c.1594A>G, ENST00000451838.1:n.964A>G, ENST00000489390.1:n.808A>G, NC_000010.11:g.111011663A>G, CM000672.2:g.111011663A>G, NC_000010.10:g.112771421A>G, CM000672.1:g.112771421A>G, NC_000010.9:g.112761411A>G, NG_028922.1:g.97121A>G, LRG_753:g.97121A>G, NM_007373.3(SHOC2):c.1594A>G (p.Ser532Gly) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1594A>G (p.Ser532Gly) variant in the SHOC2 gene is 1.147% (138/10402) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA293486/MONDO:0021060/004 0.0007 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 0, 0] 1 Uncertain Significance 2 39249922 139236 T C NM_005633.3(SOS1):c.1647A>G (p.Thr549=) 139236 CA293658 NM_005633.3:c.1647A>G, NC_000002.12:g.39022781T>C, CM000664.2:g.39022781T>C, NC_000002.11:g.39249922T>C, CM000664.1:g.39249922T>C, NC_000002.10:g.39103426T>C, NG_007530.1:g.102683A>G, LRG_754:g.102683A>G, LRG_754t1:c.1647A>G, XM_005264515.3:c.1647A>G, XM_011533060.1:c.1740A>G, XM_011533061.1:c.1740A>G, XM_011533062.1:c.1626A>G, XM_011533063.1:c.1623A>G, XM_011533064.1:c.1476A>G, XM_011533065.1:c.1740A>G, XM_011533066.1:c.582A>G, XM_005264515.4:c.1647A>G, XM_011533062.2:c.1626A>G, XM_011533064.2:c.1476A>G, ENST00000395038.6:c.1647A>G, ENST00000402219.6:c.1647A>G, ENST00000426016.5:c.1647A>G, NM_005633.3(SOS1):c.1647A>G (p.Thr549=) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.1647A>G (p.Thr549=) variant in the SOS1 gene is 0.0251% (6/10398) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA293658/MONDO:0021060/004 0.0028 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 89692854 139567 G T NM_000314.6(PTEN):c.338G>T (p.Ser113Ile) 139567 CA000405 NM_000314.6:c.338G>T, NC_000010.11:g.87933097G>T, CM000672.2:g.87933097G>T, NC_000010.10:g.89692854G>T, CM000672.1:g.89692854G>T, NC_000010.9:g.89682834G>T, NG_007466.2:g.74659G>T, LRG_311:g.74659G>T, NM_000314.5:c.338G>T, NM_001304717.2:c.857G>T, NM_001304718.1:c.-413G>T, XM_006717926.2:c.293G>T, XM_011539981.1:c.338G>T, XM_011539982.1:c.242G>T, XR_945789.1:n.1050G>T, XR_945790.1:n.1050G>T, XR_945791.1:n.1050G>T, NM_000314.7:c.338G>T, NM_001304717.5:c.857G>T, NM_001304718.2:c.-413G>T, ENST00000371953.7:c.338G>T, ENST00000498703.1:n.164G>T, ENST00000610634.1:c.236G>T, NM_000314.6(PTEN):c.338G>T (p.Ser113Ile) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], BA1 [Unmet], BS3-Supporting [MET], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.338G>T (p.S113I) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) 29706350, 25248401 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000405/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 10 89624325 140807 C G NM_000314.6(PTEN):c.79+20C>G 140807 CA000575 NM_000314.6:c.79+20C>G, NC_000010.11:g.87864568C>G, CM000672.2:g.87864568C>G, NC_000010.10:g.89624325C>G, CM000672.1:g.89624325C>G, NC_000010.9:g.89614305C>G, NG_007466.2:g.6130C>G, LRG_311:g.6130C>G, NG_033079.1:g.3870G>C, NM_000314.5:c.79+20C>G, NM_001304717.2:c.598+20C>G, NM_001304718.1:c.-627+20C>G, XM_006717926.2:c.79+20C>G, XM_011539981.1:c.79+20C>G, XR_945789.1:n.791+20C>G, XR_945790.1:n.791+20C>G, XR_945791.1:n.791+20C>G, NM_000314.7:c.79+20C>G, NM_001304717.5:c.598+20C>G, NM_001304718.2:c.-627+20C>G, ENST00000371953.7:c.79+20C>G, ENST00000462694.1:n.81+20C>G, ENST00000487939.1:n.100+20C>G, ENST00000610634.1:c.-24+20C>G, ENST00000618586.1:n.68C>G, NM_000314.6(PTEN):c.79+20C>G PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [MET], BP5 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.79+20C>G (IVS1+20C>G) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).BP7: Variant is intronic and at or beyond +7/-21, nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-11-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000575/MONDO:0017623/003 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 16 68863657 140871 C G NM_004360.4(CDH1):c.2396C>G (p.Pro799Arg) 140871 CA163797 NM_004360.4:c.2396C>G, NM_004360.3:c.2396C>G, LRG_301t1:c.2396C>G, XM_011523488.1:c.1661C>G, XM_011523489.1:c.1661C>G, NM_001317184.1:c.2213C>G, NM_001317185.1:c.848C>G, NM_001317186.1:c.431C>G, ENST00000261769.9:c.2396C>G, ENST00000422392.6:c.2213C>G, ENST00000562118.1:n.614C>G, ENST00000562836.5:n.2467C>G, ENST00000566510.5:c.*1062C>G, ENST00000566612.5:c.*636C>G, ENST00000611625.4:c.2459C>G, ENST00000612417.4:c.1853+3200C>G, ENST00000621016.4:c.1866-4449C>G, NC_000016.10:g.68829754C>G, CM000678.2:g.68829754C>G, NC_000016.9:g.68863657C>G, CM000678.1:g.68863657C>G, NC_000016.8:g.67421158C>G, NG_008021.1:g.97463C>G, LRG_301:g.97463C>G, NM_004360.4(CDH1):c.2396C>G (p.Pro799Arg) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Uncertain Significance BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [MET], PM6 [Unmet], PP3 [Unmet], PP1 [Unmet], BS2 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.2396C>G (p.Pro799Arg) variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). There is no other supporting data that meet criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: PM2. 19268661, 15173255, 22850631 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA163797/MONDO:0007648/007 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89711873 141485 A G NM_000314.6(PTEN):c.493-2A>G 141485 CA000478 NM_000314.6:c.493-2A>G, NC_000010.11:g.87952116A>G, CM000672.2:g.87952116A>G, NC_000010.10:g.89711873A>G, CM000672.1:g.89711873A>G, NC_000010.9:g.89701853A>G, NG_007466.2:g.93678A>G, LRG_311:g.93678A>G, NM_000314.5:c.493-2A>G, NM_001304717.2:c.1012-2A>G, NM_001304718.1:c.-99-2A>G, XM_006717926.2:c.448-2A>G, XM_011539981.1:c.493-2A>G, XM_011539982.1:c.397-2A>G, XR_945789.1:n.1364-2A>G, XR_945790.1:n.1481-2A>G, XR_945791.1:n.1205-5737A>G, NM_000314.7:c.493-2A>G, NM_001304717.5:c.1012-2A>G, NM_001304718.2:c.-99-2A>G, ENST00000371953.7:c.493-2A>G, NM_000314.6(PTEN):c.493-2A>G PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PVS1 [MET], PM6-Strong [MET] PTEN c.493-2A>G (IVS5-2A>G) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000222118.9)PM2: Absent in large sequenced populations. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000478/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89624275 141654 CAA C NM_000314.6(PTEN):c.50_51delAA (p.Gln17Argfs) 141654 CA000167 NM_000314.6:c.50_51delAA, NM_000314.5:c.50_51del, NM_000314.6:c.50_51del, NM_001304717.2:c.569_570del, NM_001304718.1:c.-656_-655del, XM_006717926.2:c.50_51del, XM_011539981.1:c.50_51del, XR_945789.1:n.762_763del, XR_945790.1:n.762_763del, XR_945791.1:n.762_763del, NM_000314.7:c.50_51del, NM_001304717.5:c.569_570del, NM_001304718.2:c.-656_-655del, ENST00000371953.7:c.50_51del, ENST00000462694.1:n.52_53del, ENST00000487939.1:n.71_72del, ENST00000610634.1:c.-53_-52del, ENST00000618586.1:n.19_20del, NC_000010.11:g.87864519_87864520del, CM000672.2:g.87864519_87864520del, NC_000010.10:g.89624276_89624277del, CM000672.1:g.89624276_89624277del, NC_000010.9:g.89614256_89614257del, NG_007466.2:g.6081_6082del, LRG_311:g.6081_6082del, NG_033079.1:g.3918_3919del, NM_000314.6(PTEN):c.50_51delAA (p.Gln17Argfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PVS1 [MET], PM2 [MET], PS4-Supporting [MET] PTEN c.50_51delAA (p.Q17RfsX26) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 20223021) 20223021 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000167/MONDO:0017623/003 0.9878 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68847376 141810 A G NM_004360.4(CDH1):c.1298A>G (p.Asp433Gly) 141810 CA294197 NM_004360.4:c.1298A>G, NM_004360.3:c.1298A>G, LRG_301t1:c.1298A>G, XM_011523488.1:c.563A>G, XM_011523489.1:c.563A>G, NM_001317184.1:c.1137+1210A>G, NM_001317185.1:c.-318A>G, NM_001317186.1:c.-522A>G, ENST00000261769.9:c.1298A>G, ENST00000422392.6:c.1137+1210A>G, ENST00000562836.5:n.1369A>G, ENST00000566510.5:c.1142A>G, ENST00000566612.5:c.1298A>G, ENST00000611625.4:c.1298A>G, ENST00000612417.4:c.1298A>G, ENST00000621016.4:c.1298A>G, NC_000016.10:g.68813473A>G, CM000678.2:g.68813473A>G, NC_000016.9:g.68847376A>G, CM000678.1:g.68847376A>G, NC_000016.8:g.67404877A>G, NG_008021.1:g.81182A>G, LRG_301:g.81182A>G, NM_004360.4(CDH1):c.1298A>G (p.Asp433Gly) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BP2-Strong [MET], BS2 [MET], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.1298A>G (p.Asp433Gly) variant was observed at least twice in the homozygous state in individuals without a personal and/or family history of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer (BP2_Strong; SCV000253407.6). This variant has also been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BP2_Strong, BS2. 23435907, 20921021 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA294197/MONDO:0007648/007 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89725078 142212 C T NM_000314.6(PTEN):c.1061C>T (p.Pro354Leu) 142212 CA000277 NM_000314.6:c.1061C>T, NC_000010.11:g.87965321C>T, CM000672.2:g.87965321C>T, NC_000010.10:g.89725078C>T, CM000672.1:g.89725078C>T, NC_000010.9:g.89715058C>T, NG_007466.2:g.106883C>T, LRG_311:g.106883C>T, NM_000314.5:c.1061C>T, NM_001304717.2:c.1580C>T, NM_001304718.1:c.470C>T, XM_006717926.2:c.1016C>T, XM_011539982.1:c.965C>T, XR_945791.1:n.1631C>T, NM_000314.7:c.1061C>T, NM_001304717.5:c.1580C>T, NM_001304718.2:c.470C>T, ENST00000371953.7:c.1061C>T, NM_000314.6(PTEN):c.1061C>T (p.Pro354Leu) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BS3-Supporting [MET], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] PTEN c.1061C>T (p.Pro354Leu) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) 29706350, 21869887 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000277/MONDO:0017623/003 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 89711902 142220 T A NM_000314.6(PTEN):c.520T>A (p.Tyr174Asn) 142220 CA000501 NM_000314.6:c.520T>A, NM_000314.5:c.520T>A, NM_001304717.2:c.1039T>A, NM_001304718.1:c.-72T>A, XM_006717926.2:c.475T>A, XM_011539981.1:c.520T>A, XM_011539982.1:c.424T>A, XR_945789.1:n.1391T>A, XR_945790.1:n.1508T>A, XR_945791.1:n.1205-5708T>A, NM_000314.7:c.520T>A, NM_001304717.5:c.1039T>A, NM_001304718.2:c.-72T>A, ENST00000371953.7:c.520T>A, NC_000010.11:g.87952145T>A, CM000672.2:g.87952145T>A, NC_000010.10:g.89711902T>A, CM000672.1:g.89711902T>A, NC_000010.9:g.89701882T>A, NG_007466.2:g.93707T>A, LRG_311:g.93707T>A, NM_000314.6(PTEN):c.520T>A (p.Tyr174Asn) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PP2 [MET], PS3 [MET] PTEN c.520T>A (p.Y174N)PTEN c.520T>A (p.Y174N) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 10866302)PM2: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000501/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692830 142261 G A NM_000314.6(PTEN):c.314G>A (p.Cys105Tyr) 142261 CA000393 NM_000314.6:c.314G>A, NC_000010.11:g.87933073G>A, CM000672.2:g.87933073G>A, NC_000010.10:g.89692830G>A, CM000672.1:g.89692830G>A, NC_000010.9:g.89682810G>A, NG_007466.2:g.74635G>A, LRG_311:g.74635G>A, NM_000314.5:c.314G>A, NM_001304717.2:c.833G>A, NM_001304718.1:c.-437G>A, XM_006717926.2:c.269G>A, XM_011539981.1:c.314G>A, XM_011539982.1:c.218G>A, XR_945789.1:n.1026G>A, XR_945790.1:n.1026G>A, XR_945791.1:n.1026G>A, NM_000314.7:c.314G>A, NM_001304717.5:c.833G>A, NM_001304718.2:c.-437G>A, ENST00000371953.7:c.314G>A, ENST00000498703.1:n.140G>A, ENST00000610634.1:c.212G>A, NM_000314.6(PTEN):c.314G>A (p.Cys105Tyr) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [MET], PVS1 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP4 [Unmet], PP1 [Unmet], PS4-Supporting [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.314G>A (p.Cys105Tyr) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor ClinVar Organization ID 26957) 10400993, 29706350, 15987703, 29706350, 15987703 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000393/MONDO:0017623/003 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 16 68846147 142285 C T NM_004360.4(CDH1):c.1118C>T (p.Pro373Leu) 142285 CA167953 NM_004360.4:c.1118C>T, NC_000016.10:g.68812244C>T, CM000678.2:g.68812244C>T, NC_000016.9:g.68846147C>T, CM000678.1:g.68846147C>T, NC_000016.8:g.67403648C>T, NG_008021.1:g.79953C>T, LRG_301:g.79953C>T, NM_004360.3:c.1118C>T, LRG_301t1:c.1118C>T, XM_011523488.1:c.383C>T, XM_011523489.1:c.383C>T, NM_001317184.1:c.1118C>T, NM_001317185.1:c.-498C>T, NM_001317186.1:c.-702C>T, ENST00000261769.9:c.1118C>T, ENST00000422392.6:c.1118C>T, ENST00000562836.5:n.1189C>T, ENST00000565810.1:n.162C>T, ENST00000566510.5:c.962C>T, ENST00000566612.5:c.1118C>T, ENST00000611625.4:c.1118C>T, ENST00000612417.4:c.1118C>T, ENST00000621016.4:c.1118C>T, NM_004360.4(CDH1):c.1118C>T (p.Pro373Leu) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Uncertain Significance BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [MET], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.1118C>T (p.Pro373Leu) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA167953/MONDO:0007648/007 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 10 89690790 142397 ACTTTT A NM_000314.6(PTEN):c.210-7_210-3del5 142397 CA059460 NM_000314.6:c.210-7_210-3delCTTTT, NM_000314.6:c.210-7_210-3del, NC_000010.11:g.87931039_87931043del, CM000672.2:g.87931039_87931043del, NC_000010.10:g.89690796_89690800del, CM000672.1:g.89690796_89690800del, NC_000010.9:g.89680776_89680780del, NG_007466.2:g.72601_72605del, LRG_311:g.72601_72605del, NM_000314.5:c.210-7_210-3del, NM_001304717.2:c.729-7_729-3del, NM_001304718.1:c.-541-7_-541-3del, XM_006717926.2:c.165-7_165-3del, XM_011539981.1:c.210-7_210-3del, XM_011539982.1:c.114-7_114-3del, XR_945789.1:n.922-7_922-3del, XR_945790.1:n.922-7_922-3del, XR_945791.1:n.922-7_922-3del, NM_000314.7:c.210-7_210-3del, NM_001304717.5:c.729-7_729-3del, NM_001304718.2:c.-541-7_-541-3del, ENST00000371953.7:c.210-7_210-3del, ENST00000498703.1:n.36-7_36-3del, ENST00000610634.1:c.108-7_108-3del, NM_000314.6(PTEN):c.210-7_210-3del5 PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [MET], BS4 [Unmet], BS3 [MET] PTEN c.210-7_210-3delCTTTT (IVS3-7_IVS3-3delCTTTT) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.00136 (0.14%, 14/10,306 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) 27978560, 22261759, 21659347, 15589575, 16287957, 11156385, 29360161, 26976419, 25669429, 25186627, 28677221, 27443514, 22995991, 28677221 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA059460/MONDO:0017623/003 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89720649 142423 A T NM_000314.6(PTEN):c.802-2A>T 142423 CA000591 NM_000314.6:c.802-2A>T, NC_000010.11:g.87960892A>T, CM000672.2:g.87960892A>T, NC_000010.10:g.89720649A>T, CM000672.1:g.89720649A>T, NC_000010.9:g.89710629A>T, NG_007466.2:g.102454A>T, LRG_311:g.102454A>T, NM_000314.5:c.802-2A>T, NM_001304717.2:c.1321-2A>T, NM_001304718.1:c.211-2A>T, XM_006717926.2:c.757-2A>T, XM_011539981.1:c.802-2A>T, XM_011539982.1:c.706-2A>T, XR_945791.1:n.1372-2A>T, NM_000314.7:c.802-2A>T, NM_001304717.5:c.1321-2A>T, NM_001304718.2:c.211-2A>T, ENST00000371953.7:c.802-2A>T, ENST00000472832.2:n.229-2A>T, NM_000314.6(PTEN):c.802-2A>T PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PVS1 [MET], PS4-Supporting [MET] PTEN c.802-2A>T (IVS7-2A>T) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor(s), SCV000222230.9) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000591/MONDO:0017623/003 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692819 142681 C CAAA NM_000314.6(PTEN):c.304_306dupAAA (p.Lys102_Pro103insLys) 142681 CA169101 NM_000314.6:c.304_306dupAAA, NM_000314.5:c.304_306dup, NM_000314.6:c.304_306dup, NM_001304717.2:c.823_825dup, NM_001304718.1:c.-447_-445dup, XM_006717926.2:c.259_261dup, XM_011539981.1:c.304_306dup, XM_011539982.1:c.208_210dup, XR_945789.1:n.1016_1018dup, XR_945790.1:n.1016_1018dup, XR_945791.1:n.1016_1018dup, NM_000314.7:c.304_306dup, NM_001304717.5:c.823_825dup, NM_001304718.2:c.-447_-445dup, ENST00000371953.7:c.304_306dup, ENST00000498703.1:n.130_132dup, ENST00000610634.1:c.202_204dup, NC_000010.11:g.87933063_87933065dup, CM000672.2:g.87933063_87933065dup, NC_000010.10:g.89692820_89692822dup, CM000672.1:g.89692820_89692822dup, NC_000010.9:g.89682800_89682802dup, NG_007466.2:g.74625_74627dup, LRG_311:g.74625_74627dup, NM_000314.6(PTEN):c.304_306dupAAA (p.Lys102_Pro103insLys) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET] PTEN c.304_306dupAAA (p.K102_P103insK) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-11-08 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA169101/MONDO:0017623/003 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68835596 156496 C T NM_004360.4(CDH1):c.187C>T (p.Arg63Ter) 156496 CA333496 NM_004360.4:c.187C>T, NM_004360.3:c.187C>T, LRG_301t1:c.187C>T, XM_011523488.1:c.-549C>T, XM_011523489.1:c.-549C>T, NM_001317184.1:c.187C>T, NM_001317185.1:c.-1429C>T, NM_001317186.1:c.-1633C>T, ENST00000261769.9:c.187C>T, ENST00000422392.6:c.187C>T, ENST00000562836.5:n.258C>T, ENST00000564676.5:n.469C>T, ENST00000564745.1:n.182C>T, ENST00000566510.5:c.187C>T, ENST00000566612.5:c.187C>T, ENST00000611625.4:c.187C>T, ENST00000612417.4:c.187C>T, ENST00000621016.4:c.187C>T, NC_000016.10:g.68801693C>T, CM000678.2:g.68801693C>T, NC_000016.9:g.68835596C>T, CM000678.1:g.68835596C>T, NC_000016.8:g.67393097C>T, NG_008021.1:g.69402C>T, LRG_301:g.69402C>T, NM_004360.4(CDH1):c.187C>T (p.Arg63Ter) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [MET], PM2 [MET], PM6 [Unmet], PP1 [Unmet], PP3 [Unmet], BS2 [Unmet], PS4-Supporting [MET], PM4 [Unmet], BP2 [Unmet], BP4 [Unmet], BA1 [Unmet], PS3 [Unmet], PS2 [Unmet], PS1 [Unmet] The c.187C>T (p.Arg63*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 9751616). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1, PM2, PS4_Supporting. 9751616 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA333496/MONDO:0007648/007 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68863655 156497 TC T NM_004360.4(CDH1):c.2398delC (p.Arg800Alafs) 156497 CA281459 NM_004360.4:c.2398delC, NC_000016.10:g.68829756del, CM000678.2:g.68829756del, NC_000016.9:g.68863659del, CM000678.1:g.68863659del, NC_000016.8:g.67421160del, NG_008021.1:g.97465del, LRG_301:g.97465del, NM_004360.3:c.2398del, LRG_301t1:c.2398del, XM_011523488.1:c.1663del, XM_011523489.1:c.1663del, NM_001317184.1:c.2215del, NM_001317185.1:c.850del, NM_001317186.1:c.433del, NM_004360.4:c.2398del, ENST00000261769.9:c.2398del, ENST00000422392.6:c.2215del, ENST00000562118.1:n.616del, ENST00000562836.5:n.2469del, ENST00000566510.5:c.*1064del, ENST00000566612.5:c.*638del, ENST00000611625.4:c.2461del, ENST00000612417.4:c.1853+3202del, ENST00000621016.4:c.1866-4447del, NM_004360.4(CDH1):c.2398delC (p.Arg800Alafs) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP1 [MET], PP3 [Unmet], PM4 [Unmet], PVS1-Strong [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS4 [MET], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet] The c.2398delC (p.Arg800Alafs*16) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 17545690). This variant was also found to co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed (PP1; PMID: 17545690). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Strong, PM2, PS4, PP1. 17545690, 17545690, 18427545, 17545690 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA281459/MONDO:0007648/007 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68846166 156499 G A NM_004360.4(CDH1):c.1137G>A (p.Thr379=) 156499 CA186229 NM_004360.4:c.1137G>A, NM_004360.3:c.1137G>A, LRG_301t1:c.1137G>A, XM_011523488.1:c.402G>A, XM_011523489.1:c.402G>A, NM_001317184.1:c.1137G>A, NM_001317185.1:c.-479G>A, NM_001317186.1:c.-683G>A, ENST00000261769.9:c.1137G>A, ENST00000422392.6:c.1137G>A, ENST00000562836.5:n.1208G>A, ENST00000565810.1:n.181G>A, ENST00000566510.5:c.981G>A, ENST00000566612.5:c.1137G>A, ENST00000611625.4:c.1137G>A, ENST00000612417.4:c.1137G>A, ENST00000621016.4:c.1137G>A, NC_000016.10:g.68812263G>A, CM000678.2:g.68812263G>A, NC_000016.9:g.68846166G>A, CM000678.1:g.68846166G>A, NC_000016.8:g.67403667G>A, NG_008021.1:g.79972G>A, LRG_301:g.79972G>A, NM_004360.4(CDH1):c.1137G>A (p.Thr379=) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PM2 [MET], PM6 [Unmet], PP3 [Unmet], PP1 [Unmet], BS2 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [MET], PS4 [MET], PS2 [Unmet], PVS1-Moderate [MET] The c.1137G>A p.(Thr379=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). The variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 15831593). Additionally, this variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 15831593, 17545690, 17221870, 21681551, 27995193). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Moderate, PM2, PS3, PS4. 15831593, 18427545, 15831593, 18427545, 17221870, 15831593, 17545690, 21681551, 27995193 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA186229/MONDO:0007648/007 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763614 158604 A G NM_004004.5(GJB2):c.107T>C (p.Leu36Pro) 158604 CA172208 NM_004004.5:c.107T>C, NC_000013.11:g.20189475A>G, CM000675.2:g.20189475A>G, NC_000013.10:g.20763614A>G, CM000675.1:g.20763614A>G, NC_000013.9:g.19661614A>G, NG_008358.1:g.8501T>C, XM_011535049.1:c.107T>C, XM_011535049.2:c.107T>C, NM_004004.6:c.107T>C, ENST00000382844.1:c.107T>C, ENST00000382848.4:c.107T>C, NM_004004.5(GJB2):c.107T>C (p.Leu36Pro) GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Uncertain Significance PVS1 [Unmet], PP3 [MET], PM2-Supporting [MET], BP4 [Unmet], BA1 [Unmet], PS1 [Unmet], PM5 [Unmet], PM3 [MET], BP7 [Unmet], BS1 [Unmet] The allele frequency of the p.Leu36Pro variant in the GJB2 gene is 0.01% (2/19954) of East Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.945, which is above the threshold necessary to apply PP3. This variant has been detected in one patient with hearing loss in trans with 35delG (PM3; PMID:16125251). The variant has also been reported in three individuals with no pathogenic variant found in trans (PMIDs: 17666888, 26043044). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP3, PM3. 16125251, 26043044, 17666888 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA172208/MONDO:0019497/005 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 73572580 162956 G A NM_022124.5(CDH23):c.9566G>A (p.Arg3189Gln) 162956 CA175533 NM_022124.5:c.9566G>A, NM_001171933.1:c.2846G>A, NM_001171934.1:c.2846G>A, NM_001171935.1:c.257G>A, NM_001171936.1:c.257G>A, XM_006717940.2:c.9761G>A, XM_006717942.2:c.9695G>A, XM_011540039.1:c.9758G>A, XM_011540040.1:c.9755G>A, XM_011540041.1:c.9701G>A, XM_011540042.1:c.9671G>A, XM_011540043.1:c.9761G>A, XM_011540044.1:c.9626G>A, XM_011540045.1:c.9761G>A, XM_011540046.1:c.9221G>A, XM_011540047.1:c.8579G>A, XM_011540052.1:c.6089G>A, ENST00000224721.10:c.9581G>A, ENST00000398788.4:c.2846G>A, ENST00000475158.1:n.3102G>A, ENST00000619887.4:c.2846G>A, ENST00000622827.4:c.9566G>A, NC_000010.11:g.71812823G>A, CM000672.2:g.71812823G>A, NC_000010.10:g.73572580G>A, CM000672.1:g.73572580G>A, NC_000010.9:g.73242586G>A, NG_008835.1:g.420877G>A, NM_022124.5(CDH23):c.9566G>A (p.Arg3189Gln) CDH23 Usher syndrome MONDO:0019501 Autosomal recessive inheritance Uncertain Significance PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP4 [Unmet], PP1 [Unmet], BS2 [Unmet], PM2-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], PS2 [Unmet], PS4 [Unmet], PS3 [Unmet], PS1 [Unmet], PM1 [Unmet], PM3 [Unmet], PM4 [Unmet], PM5 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The c.9566G>A (p.Arg3189Gln) variant in CDH23 has been identified in 1 heterozygous patient with sensorineural hearing loss (Partners LMM internal data, SCV000197429.4). The allele frequency of the variant is 0.023% (7/30608) of South Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : PM2_Supporting. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA175533/MONDO:0019501/005 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 6 76599951 164639 C T NM_004999.3(MYO6):c.2836C>T (p.Arg946Cys) 164639 CA177354 NM_004999.3:c.2836C>T, NC_000006.12:g.75890234C>T, CM000668.2:g.75890234C>T, NC_000006.11:g.76599951C>T, CM000668.1:g.76599951C>T, NC_000006.10:g.76656671C>T, NG_009934.1:g.146043C>T, NG_009934.2:g.146042C>T, NM_001300899.1:c.2836C>T, XM_005248719.2:c.2836C>T, XM_005248720.2:c.2836C>T, XM_005248721.2:c.2836C>T, XM_005248722.2:c.2836C>T, XM_005248724.2:c.2836C>T, XM_005248726.2:c.2836C>T, XM_005248719.4:c.2836C>T, XM_005248720.4:c.2836C>T, XM_005248721.4:c.2836C>T, XM_005248722.4:c.2836C>T, XM_005248724.4:c.2836C>T, XM_005248726.4:c.2836C>T, XM_017010899.2:c.2836C>T, XM_024446447.1:c.2836C>T, XM_024446448.1:c.2836C>T, NM_004999.4:c.2836C>T, ENST00000369975.5:c.2836C>T, ENST00000369977.7:c.2836C>T, ENST00000369981.7:c.2836C>T, ENST00000369985.8:c.2836C>T, ENST00000430435.1:n.25C>T, ENST00000615563.4:c.2836C>T, ENST00000627432.2:c.2836C>T, NM_004999.3(MYO6):c.2836C>T (p.Arg946Cys) MYO6 nonsyndromic genetic deafness MONDO:0019497 Likely Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [MET], BS4 [Unmet] The filtering allele frequency of the p.Arg946Cys variant in the MYO6 gene is 0.095% (39/30776) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (BS1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA177354/MONDO:0019497/005 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 11 121039471 165370 T C NM_005422.2(TECTA):c.5836T>C (p.Tyr1946His) 165370 CA178113 NM_005422.2:c.5836T>C, NM_005422.2:n.5836T>C, ENST00000264037.2:n.5836T>C, ENST00000392793.5:c.5836T>C, NC_000011.10:g.121168762T>C, CM000673.2:g.121168762T>C, NC_000011.9:g.121039471T>C, CM000673.1:g.121039471T>C, NC_000011.8:g.120544681T>C, NG_011633.1:g.71097T>C, NM_005422.2(TECTA):c.5836T>C (p.Tyr1946His) TECTA nonsyndromic genetic deafness MONDO:0019497 Likely Benign PP3 [MET], BS1 [MET] The filtering allele frequency of the c.5836T>C (p.Tyr1946His) variant in the TECTA gene is 0.495% for Ashkenazi Jewish chromosomes by gnomAD (64/10370 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL EP) for autosomal recessive hearing loss variants (BS1). The REVEL computational prediction analysis tool produced a score of 0.8, which is above the threshold necessary to apply PP3. The HL EP allows classification of variants as likely benign with only BS1 if no other criteria are in conflict. The HL EP reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in this case since computational scores are error prone, especially when predicting pathogenicity. In summary, the HL EP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, PP3. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA178113/MONDO:0019497/005 0.3246 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 1 215848748 166435 T C NM_206933.2(USH2A):c.12505A>G (p.Thr4169Ala) 166435 CA179513 NM_206933.2:c.12505A>G, NM_206933.3:c.12505A>G, ENST00000307340.7:c.12505A>G, NC_000001.11:g.215675406T>C, CM000663.2:g.215675406T>C, NC_000001.10:g.215848748T>C, CM000663.1:g.215848748T>C, NC_000001.9:g.213915371T>C, NG_009497.1:g.752991A>G, NM_206933.2(USH2A):c.12505A>G (p.Thr4169Ala) USH2A Usher syndrome type 2 MONDO:0016484 Autosomal recessive inheritance Likely Benign PP3 [Unmet], PP4 [Unmet], BS2 [Unmet], BA1 [Unmet], BP4 [MET], BS1 [MET] The filtering allele frequency of the p.Thr4169Ala variant in the USH2A gene is 0.32% for African chromosomes by gnomAD (82/24940 with 95% CI) (BS1). Computational predictors for the variant suggest no impact on the gene or gene product (REVEL score: 0.207) (BP4). Of note, this variant was reported in 4 patients with Usher syndrome (PMID:28041643) though without any convincing evidence for pathogenicity (PM3 not met). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS1 and BP4 28041643 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA179513/MONDO:0016484/005 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 1 216258168 166499 T C NM_206933.2(USH2A):c.5039A>G (p.Lys1680Arg) 166499 CA179559 NM_206933.2:c.5039A>G, NC_000001.11:g.216084826T>C, CM000663.2:g.216084826T>C, NC_000001.10:g.216258168T>C, CM000663.1:g.216258168T>C, NC_000001.9:g.214324791T>C, NG_009497.1:g.343571A>G, NR_125992.1:n.266-1896T>C, NR_125993.1:n.137-1896T>C, NM_206933.3:c.5039A>G, ENST00000307340.7:c.5039A>G, ENST00000463147.1:n.283A>G, ENST00000481786.1:n.281A>G, NM_206933.2(USH2A):c.5039A>G (p.Lys1680Arg) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Uncertain Significance PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], PM2-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] The c.5039A>G (p.Lys1680Arg) variant in USH2A has been observed in the heterozygous state in one individual with hearing loss (PS4 not met; Partners LMM ClinVar SCV000201911.4). The allele frequency of the p.Lys1680Arg variant is 0.05% (20/34286) of Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). In summary, this variant meets criteria to be classified as a variant of uncertain clinical significance for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA179559/MONDO:0019501/005 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 1 216348710 166504 C CT NM_206933.2(USH2A):c.4510dupA (p.Arg1504Lysfs) 166504 CA273289 NM_206933.2:c.4510_4511insA, NM_206933.2:c.4510dupA, NM_007123.5:c.4510dup, NM_206933.2:c.4510dup, NM_206933.3:c.4510dup, ENST00000307340.7:c.4510dup, ENST00000366942.3:c.4510dup, NC_000001.11:g.216175371dup, CM000663.2:g.216175371dup, NC_000001.10:g.216348713dup, CM000663.1:g.216348713dup, NC_000001.9:g.214415336dup, NG_009497.1:g.253028dup, NM_206933.2(USH2A):c.4510dupA (p.Arg1504Lysfs) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [MET], BS2 [Unmet], BA1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS4 [Unmet], PS3 [Unmet], PS2 [Unmet], PM3-Strong [MET], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The c.4510dupA (p.Arg1504LysX26) variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 21/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in 2 patients with hearing loss in trans with 2 different pathogenic variants (PM3_S; PMID:22135276). The allele frequency of the p.Arg1504LysX26 variant in the USH2A gene is 0.003% (3/111138) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). At least one patient with a variant in this gene displayed features of retinitis pigmentosa (PP4; PMID: 22135276). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_S, PM2, PP4. 22135276, 10729113, 15325563, 28041643, 22135276 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA273289/MONDO:0019501/005 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 11 76890889 177732 G A NM_000260.3(MYO7A):c.2476G>A (p.Ala826Thr) 177732 CA180669 NM_000260.3:c.2476G>A, NC_000011.10:g.77179843G>A, CM000673.2:g.77179843G>A, NC_000011.9:g.76890889G>A, CM000673.1:g.76890889G>A, NC_000011.8:g.76568537G>A, NG_009086.1:g.56580G>A, NM_001127179.2:c.2476G>A, NM_001127180.1:c.2476G>A, XM_005274012.2:c.2476G>A, XM_006718558.2:c.2476G>A, XM_006718559.2:c.2476G>A, XM_006718560.2:c.2476G>A, XM_006718561.2:c.2476G>A, XM_011545044.1:c.2476G>A, XM_011545045.1:c.2476G>A, XM_011545046.1:c.2443G>A, XM_011545047.1:c.2476G>A, XM_011545048.1:c.2368-531G>A, XM_011545049.1:c.2245G>A, XM_011545050.1:c.2218G>A, XM_011545051.1:c.2476G>A, XM_011545052.1:c.2476G>A, XR_949938.1:n.2796G>A, XR_949941.1:n.2796G>A, XR_949942.1:n.2798G>A, XR_949943.1:n.2798G>A, XM_011545044.2:c.2476G>A, XM_011545046.2:c.2566G>A, XM_011545050.2:c.2218G>A, XM_017017778.1:c.2566G>A, XM_017017779.1:c.2566G>A, XM_017017780.1:c.2566G>A, XM_017017781.1:c.2566G>A, XM_017017782.1:c.2566G>A, XM_017017783.1:c.2566G>A, XM_017017784.1:c.2566G>A, XM_017017785.1:c.2335G>A, XM_017017786.1:c.2566G>A, XM_017017787.1:c.2566G>A, XM_017017788.1:c.2566G>A, XR_001747885.1:n.2581G>A, XR_001747886.1:n.2581G>A, XR_001747887.1:n.2581G>A, XR_001747888.1:n.2581G>A, XR_001747889.1:n.2581G>A, NM_000260.4:c.2476G>A, ENST00000409619.6:c.2443G>A, ENST00000409709.7:c.2476G>A, ENST00000409893.5:c.2476G>A, ENST00000458169.2:n.19G>A, ENST00000458637.6:c.2476G>A, ENST00000481328.7:n.19G>A, ENST00000620575.4:c.2476G>A, NM_000260.3(MYO7A):c.2476G>A (p.Ala826Thr) MYO7A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Uncertain Significance BS2 [Unmet], PP3 [Unmet], PP1 [MET], PP4 [MET], BP4 [Unmet], BA1 [MET], PS1 [Unmet], PS4 [Unmet], PM5 [Unmet], PM3 [MET] The c.2476G>A (p.Ala826Thr) variant in MYO7A has been detected in 2 patients with Usher syndrome in trans with pathogenic variants, and has been observed as homozygous in at least 9 cases (PM3; PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). It has been reported to segregate with Usher syndrome in at least 12 family members (PP1_Strong; 23770805, 9382091). In most of these cases, the patients were documented to have both hearing loss and retinitis pigmentosa (PP4; PMID:27460420, 29490346, 23770805, 22135276, 9382091). The filtering allele frequency of the p.Ala826Thr variant in the MYO7A gene is 0.55% for South Asian chromosomes by gnomAD, including 1 homozygous observation (144/22680 with 95% CI) and this variant is not statistically enriched in cohorts of Usher (0.8%; Fisher’s exact p value =0.3262) when compared to the South Asian population in gnomAD (0.55%) (PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). Due to the lack of adequately large case-control analyses in the South Asian population, the ClinGen Hearing Loss Expert Panel believes that the evidence for this variant is inconclusive. In summary, this variant meets criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the HL EP-specified ACMG/AMP criteria applied: BA1, PM3, PP1, PP4. 23770805, 9382091, 23770805, 9382091, 27460420, 29490346, 22135276, 18181211 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA180669/MONDO:0019501/005 0.025 Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 1 215824001 177913 C T NM_206933.2(USH2A):c.14276G>A (p.Gly4759Glu) 177913 CA180987 NM_206933.2:c.14276G>A, NM_206933.3:c.14276G>A, ENST00000307340.7:c.14276G>A, NC_000001.11:g.215650659C>T, CM000663.2:g.215650659C>T, NC_000001.10:g.215824001C>T, CM000663.1:g.215824001C>T, NC_000001.9:g.213890624C>T, NG_009497.1:g.777738G>A, NM_206933.2(USH2A):c.14276G>A (p.Gly4759Glu) USH2A Usher syndrome type 2A MONDO:0010169 Autosomal recessive inheritance Likely Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], PP1 [Unmet], PP4 [Unmet], PP3 [Unmet], BS2 [Unmet], BA1 [Unmet], BP2 [Unmet], BP4 [MET], BP3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], PS1 [Unmet], PM3 [Unmet], PM1 [Unmet], PM5 [Unmet], PM4 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [MET], BS4 [Unmet] The c.14276G>A (p.Gly4759Glu) variant has been detected in at least 4 heterozygous individuals with clinical features of hearing loss or retinitis pigmentosa (PS4/PM3 not met; Partners LMM internal data, PMID 28041643). However, the filtering allele frequency (the lower threshold of the 95% CI of 102/24022) of the p.Gly4759Glu variant in the USH2A gene is 0.425% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). 28041643, 28041643 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA180987/MONDO:0010169/005 0.3246 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 0, 0] 2 Uncertain Significance 11 120984338 178532 A G NM_005422.2(TECTA):c.701A>G (p.Gln234Arg) 178532 CA182505 NM_005422.2:c.701A>G, NC_000011.10:g.121113629A>G, CM000673.2:g.121113629A>G, NC_000011.9:g.120984338A>G, CM000673.1:g.120984338A>G, NC_000011.8:g.120489548A>G, NG_011633.1:g.15964A>G, NM_005422.2:n.701A>G, ENST00000264037.2:n.701A>G, ENST00000392793.5:c.701A>G, NM_005422.2(TECTA):c.701A>G (p.Gln234Arg) TECTA nonsyndromic genetic deafness MONDO:0019497 Likely Benign PM2 [Unmet], PVS1 [Unmet], PP3 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PM4 [Unmet], BS1 [MET] The filtering allele frequency of the c.701A>G (p.Gln234Arg) variant in the TECTA gene is 0.37% (104/23994) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA182505/MONDO:0019497/005 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 11 121008285 178538 C T NM_005422.2(TECTA):c.3097C>T (p.Arg1033Trp) 178538 CA182517 NM_005422.2:c.3097C>T, NM_005422.2:n.3097C>T, ENST00000264037.2:n.3097C>T, ENST00000392793.5:c.3097C>T, NC_000011.10:g.121137576C>T, CM000673.2:g.121137576C>T, NC_000011.9:g.121008285C>T, CM000673.1:g.121008285C>T, NC_000011.8:g.120513495C>T, NG_011633.1:g.39911C>T, NM_005422.2(TECTA):c.3097C>T (p.Arg1033Trp) TECTA nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Likely Benign PM2 [Unmet], PVS1 [Unmet], PP3 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PM5 [Unmet], PM4 [Unmet], PM3 [Unmet], BP7 [Unmet], BS1 [MET] The filtering allele frequency (the lower threshold of the 95% CI of 88/24956) of the p.Arg1033Trp variant in the TECTA gene is 0.29% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The p.Arg1033Trp variant has been identified in one hearing loss patient who carries a second TECTA variant, p.Gln234Arg, that has previously been classified as likely benign by the HL VCEP (PMID 26969326, SCV000840522.3). The variant has also been observed by Partners LMM in one homozygous patient, two heterozygous patients, and two compound heterozygous patients who also carry one or two pathogenic or VUS favor-pathogenic variants. These cases are inconclusive (SCV000204966.4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. 26969326, 26969326 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA182517/MONDO:0019497/005 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 11 121008680 178539 C T NM_005422.2(TECTA):c.3492C>T (p.Thr1164=) 178539 CA182519 NM_005422.2:c.3492C>T, NM_005422.2:n.3492C>T, ENST00000264037.2:n.3492C>T, ENST00000392793.5:c.3492C>T, NC_000011.10:g.121137971C>T, CM000673.2:g.121137971C>T, NC_000011.9:g.121008680C>T, CM000673.1:g.121008680C>T, NC_000011.8:g.120513890C>T, NG_011633.1:g.40306C>T, NM_005422.2(TECTA):c.3492C>T (p.Thr1164=) TECTA nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Likely Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BP4 [MET], BP2 [Unmet], BP3 [Unmet], BA1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], PS1 [Unmet], PM3 [Unmet], PM1 [Unmet], PM4 [Unmet], PM5 [Unmet], BP7 [MET], BP5 [Unmet], BS1 [MET], BS4 [Unmet] The filtering allele frequency of the c.3492C>T (p.Thr1164=) variant in the TECTA gene is 0.423% for African chromosomes by gnomAD (123/23960) with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The silent p.Thr1164= variant in TECTA is not predicted by MaxEntScan to impact splicing (BP7, BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, BP7, BP4. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA182519/MONDO:0019497/005 0.4999 VUS Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 11 120996243 178638 C T NM_005422.2(TECTA):c.1436C>T (p.Pro479Leu) 178638 CA182711 NM_005422.2:c.1436C>T, NC_000011.10:g.121125534C>T, CM000673.2:g.121125534C>T, NC_000011.9:g.120996243C>T, CM000673.1:g.120996243C>T, NC_000011.8:g.120501453C>T, NG_011633.1:g.27869C>T, NM_005422.2:n.1436C>T, ENST00000264037.2:n.1436C>T, ENST00000392793.5:c.1436C>T, NM_005422.2(TECTA):c.1436C>T (p.Pro479Leu) TECTA nonsyndromic genetic deafness MONDO:0019497 Benign BA1 [MET] The filtering allele frequency of the c.1436C>T (p.Pro479Leu) variant in the TECTA gene is 0.63% (219/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-17 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA182711/MONDO:0019497/005 0.025 Likely Benign Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 3 12641168 178666 AAAGGGAGGGCCCC A NM_002880.3(RAF1):c.1108+9_1108+21delGGGGCCCTCCCTT 178666 CA182757 NM_002880.3:c.1108+9_1108+21del, NM_002880.3:c.1108+9_1108+21delGGGGCCCTCCCTT, NC_000003.12:g.12599673_12599685del, CM000665.2:g.12599673_12599685del, NC_000003.11:g.12641172_12641184del, CM000665.1:g.12641172_12641184del, NC_000003.10:g.12616172_12616184del, NG_007467.1:g.69498_69510del, LRG_413:g.69498_69510del, LRG_413t1:c.1108+9_1108+21del, XM_005265355.1:c.1108+9_1108+21del, XM_005265357.1:c.1009+9_1009+21del, XM_005265358.3:c.865+9_865+21del, XM_005265359.3:c.766+9_766+21del, XM_005265360.1:c.1108+9_1108+21del, XM_011533974.1:c.1108+9_1108+21del, XM_011533975.1:c.865+9_865+21del, NM_001354689.1:c.1168+9_1168+21del, NM_001354690.1:c.1108+9_1108+21del, NM_001354691.1:c.865+9_865+21del, NM_001354692.1:c.865+9_865+21del, NM_001354693.1:c.1009+9_1009+21del, NM_001354694.1:c.925+9_925+21del, NM_001354695.1:c.766+9_766+21del, NR_148940.1:n.1523+9_1523+21del, NR_148941.1:n.1523+9_1523+21del, NR_148942.1:n.1521+9_1521+21del, XM_011533974.3:c.1108+9_1108+21del, XM_017006966.1:c.1009+9_1009+21del, XR_001740227.1:n.1340+9_1340+21del, ENST00000251849.8:c.1108+9_1108+21del, ENST00000423275.5:c.*785+9_*785+21del, ENST00000432427.2:n.745+9_745+21del, ENST00000442415.6:c.1168+9_1168+21del, ENST00000460610.1:n.65+9_65+21del, ENST00000465826.5:n.352+9_352+21del, NM_002880.3(RAF1):c.1108+9_1108+21delGGGGCCCTCCCTT RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BP7 [MET], BP5 [MET], BA1 [MET] The c.1108+9_1108+21del variant in the RAF1 gene has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR Lab ID's: 26957, 21766; ClinVar SCV000205113.4, SCV000209007.2). This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The filtering allele frequency of the c.1108+9_1108+21del variant in the RAF1 gene is 0.0637% (54/66698) for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BA1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5, BP7. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA182757/MONDO:0021060/004 0.0059 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 6 76538307 178957 C T NM_004999.3(MYO6):c.238C>T (p.Arg80Ter) 178957 CA183381 NM_004999.3:c.238C>T, NC_000006.12:g.75828590C>T, CM000668.2:g.75828590C>T, NC_000006.11:g.76538307C>T, CM000668.1:g.76538307C>T, NC_000006.10:g.76595027C>T, NG_009934.1:g.84399C>T, NG_009934.2:g.84398C>T, NM_001300899.1:c.238C>T, XM_005248719.2:c.238C>T, XM_005248720.2:c.238C>T, XM_005248721.2:c.238C>T, XM_005248722.2:c.238C>T, XM_005248724.2:c.238C>T, XM_005248726.2:c.238C>T, XM_005248719.4:c.238C>T, XM_005248720.4:c.238C>T, XM_005248721.4:c.238C>T, XM_005248722.4:c.238C>T, XM_005248724.4:c.238C>T, XM_005248726.4:c.238C>T, XM_017010899.2:c.238C>T, XM_024446447.1:c.238C>T, XM_024446448.1:c.238C>T, NM_004999.4:c.238C>T, ENST00000369975.5:c.238C>T, ENST00000369977.7:c.238C>T, ENST00000369981.7:c.238C>T, ENST00000369985.8:c.238C>T, ENST00000615563.4:c.238C>T, ENST00000627432.2:c.238C>T, NM_004999.3(MYO6):c.238C>T (p.Arg80Ter) MYO6 nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], BS2 [Unmet], PP4 [Unmet], PP1 [Unmet], PP3 [Unmet], BP2 [Unmet], BP4 [Unmet], BP3 [Unmet], BA1 [Unmet], PS2 [Unmet], PS4 [Unmet], PS3 [Unmet], PS1 [Unmet], PM3 [Unmet], PM1 [Unmet], PM5 [Unmet], PM4 [Unmet], BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet] The p.Arg80Ter variant in MYO6 is predicted to cause a premature stop codon in biologically-relevant-exon 4 of a total of 35 exons, and is expected to lead to a truncated or absent protein. Loss of function in MYO6 is an established disease mechanism for autosomal dominant hearing loss (PVS1). The allele frequency of this variant is 0.0009% (1/111322) of European chromosomes by the Genome Aggregation Database ( http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (PM2). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: (PVS1, PM2). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-11 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA183381/MONDO:0019497/005 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 1 216061814 179542 C T NM_206933.2(USH2A):c.8177G>A (p.Gly2726Glu) 179542 CA184631 NM_206933.2:c.8177G>A, NM_206933.3:c.8177G>A, ENST00000307340.7:c.8177G>A, NC_000001.11:g.215888472C>T, CM000663.2:g.215888472C>T, NC_000001.10:g.216061814C>T, CM000663.1:g.216061814C>T, NC_000001.9:g.214128437C>T, NG_009497.1:g.539925G>A, NM_206933.2(USH2A):c.8177G>A (p.Gly2726Glu) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The p.Gly2726Glu variant in USH2A was identified in 0.003% (3/111282) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel autosomal recessive hearing loss (PM2). In summary, the clinical significance of this variant is uncertain. ACMG/AMG criteria applied: PM2. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA184631/MONDO:0019501/005 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 7 140501333 180784 A G NM_004333.4(BRAF):c.739T>C (p.Phe247Leu) 180784 CA295904 NM_004333.4:c.739T>C, NC_000007.14:g.140801533A>G, CM000669.2:g.140801533A>G, NC_000007.13:g.140501333A>G, CM000669.1:g.140501333A>G, NC_000007.12:g.140147802A>G, NG_007873.3:g.128232T>C, LRG_299:g.128232T>C, LRG_299t1:c.739T>C, XM_005250045.1:c.739T>C, XM_005250046.1:c.739T>C, XM_011516529.1:c.739T>C, XM_011516530.1:c.739T>C, XR_242190.1:n.747T>C, XR_927520.1:n.747T>C, XR_927521.1:n.747T>C, XR_927522.1:n.747T>C, XR_927523.1:n.747T>C, NM_001354609.1:c.739T>C, NM_004333.5:c.739T>C, NR_148928.1:n.1044T>C, XM_017012558.1:c.739T>C, XM_017012559.1:c.739T>C, XR_001744857.1:n.747T>C, XR_001744858.1:n.747T>C, ENST00000288602.10:c.739T>C, ENST00000497784.1:n.774T>C, NM_004333.4(BRAF):c.739T>C (p.Phe247Leu) BRAF RASopathy MONDO:0021060 Autosomal dominant inheritance Pathogenic BS2 [Unmet], PP1 [Unmet], PP2 [MET], PP3 [MET], PM1 [MET], PM4 [Unmet], PM5 [Unmet], PS3 [MET], PS2 [Unmet], PS4 [Unmet], PS1 [MET], BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM2 [MET], PM6 [MET], BP2 [Unmet], BP3 [Unmet], BP1 [Unmet], BP4 [Unmet], BA1 [Unmet] The c.739T>C (p.Phe247Leu) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx internal data; GTR Lab ID: 26957; ClinVar SCV000207748.12). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID: 28512244). The c.739T>C variant results in the same amino acid change as the previously established pathogenic c.741T>G (p.Phe247Leu) variant (PS1; ClinVar ID 55793). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe247Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM2, PS3, PS1, PM1, PP2, PP3. 28512244, 26243863, 22899370 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA295904/MONDO:0021060/004 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 19 4101272 180905 G A NM_030662.3(MAP2K2):c.535C>T (p.Arg179Trp) 180905 CA296130 NM_030662.3:c.535C>T, LRG_750t1:c.535C>T, XM_006722799.2:c.535C>T, XM_011528133.1:c.-36C>T, XM_017026989.1:c.535C>T, XM_017026990.1:c.535C>T, XM_017026991.1:c.535C>T, ENST00000262948.9:c.535C>T, ENST00000394867.8:c.244C>T, ENST00000593364.5:n.482C>T, ENST00000597008.5:n.136C>T, ENST00000599345.1:n.805C>T, ENST00000601786.5:n.836C>T, ENST00000602167.5:n.255C>T, NC_000019.10:g.4101274G>A, CM000681.2:g.4101274G>A, NC_000019.9:g.4101272G>A, CM000681.1:g.4101272G>A, NC_000019.8:g.4052272G>A, NG_007996.1:g.27855C>T, LRG_750:g.27855C>T, NM_030662.3(MAP2K2):c.535C>T (p.Arg179Trp) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.535C>T (p.Arg179Trp) variant in the MAP2K2 gene is 0.0362% (3/2258) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA296130/MONDO:0021060/004 0.025 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 3 12633259 181509 C T NM_002880.3(RAF1):c.1141G>A (p.Asp381Asn) 181509 CA297118 NM_002880.3:c.1141G>A, LRG_413t1:c.1141G>A, XM_005265355.1:c.1141G>A, XM_005265357.1:c.1042G>A, XM_005265358.3:c.898G>A, XM_005265359.3:c.799G>A, XM_005265360.1:c.1141G>A, XM_011533974.1:c.1141G>A, XM_011533975.1:c.898G>A, NM_001354689.1:c.1201G>A, NM_001354690.1:c.1141G>A, NM_001354691.1:c.898G>A, NM_001354692.1:c.898G>A, NM_001354693.1:c.1042G>A, NM_001354694.1:c.958G>A, NM_001354695.1:c.799G>A, NR_148940.1:n.1669G>A, NR_148941.1:n.1615G>A, NR_148942.1:n.1554G>A, XM_011533974.3:c.1141G>A, XM_017006966.1:c.1042G>A, XR_001740227.1:n.1432G>A, ENST00000251849.8:c.1141G>A, ENST00000423275.5:c.*818G>A, ENST00000432427.2:n.778G>A, ENST00000442415.6:c.1201G>A, ENST00000460610.1:n.98G>A, ENST00000465826.5:n.498G>A, ENST00000475353.1:n.309G>A, ENST00000494557.1:n.157G>A, NC_000003.12:g.12591760C>T, CM000665.2:g.12591760C>T, NC_000003.11:g.12633259C>T, CM000665.1:g.12633259C>T, NC_000003.10:g.12608259C>T, NG_007467.1:g.77420G>A, LRG_413:g.77420G>A, NM_002880.3(RAF1):c.1141G>A (p.Asp381Asn) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1141G>A (p.Asp381Asn) variant in the RAF1 gene is 0.162% (36/16508) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA297118/MONDO:0021060/004 0.0122 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 112724154 181526 A C NM_007373.3(SHOC2):c.38A>C (p.Glu13Ala) 181526 CA297169 NM_007373.3:c.38A>C, NC_000010.11:g.110964396A>C, CM000672.2:g.110964396A>C, NC_000010.10:g.112724154A>C, CM000672.1:g.112724154A>C, NC_000010.9:g.112714144A>C, NG_028922.1:g.49854A>C, LRG_753:g.49854A>C, NM_001269039.1:c.38A>C, LRG_753t1:c.38A>C, XM_011540216.1:c.-380-21232A>C, NM_001269039.2:c.38A>C, NM_001324336.1:c.38A>C, NM_001324337.1:c.38A>C, NR_136749.1:n.116-21232A>C, ENST00000265277.9:c.38A>C, ENST00000369452.8:c.38A>C, ENST00000480155.1:n.522A>C, ENST00000489390.1:n.56-36019A>C, ENST00000489783.1:n.416A>C, NM_007373.3(SHOC2):c.38A>C (p.Glu13Ala) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET], BA1 [Unmet] The filtering allele frequency of the c.38A>C (p.Glu13Ala) variant in the SHOC2 gene is 0.0484% (10/11206) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA297169/MONDO:0021060/004 0.0028 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 112724635 181528 G A NM_007373.3(SHOC2):c.519G>A (p.Met173Ile) 181528 CA199174 NM_007373.3:c.519G>A, NC_000010.11:g.110964877G>A, CM000672.2:g.110964877G>A, NC_000010.10:g.112724635G>A, CM000672.1:g.112724635G>A, NC_000010.9:g.112714625G>A, NG_028922.1:g.50335G>A, LRG_753:g.50335G>A, NM_001269039.1:c.519G>A, LRG_753t1:c.519G>A, XM_011540216.1:c.-380-20751G>A, NM_001269039.2:c.519G>A, NM_001324336.1:c.519G>A, NM_001324337.1:c.519G>A, NR_136749.1:n.116-20751G>A, ENST00000265277.9:c.519G>A, ENST00000369452.8:c.519G>A, ENST00000451838.1:n.27G>A, ENST00000489390.1:n.56-35538G>A, NM_007373.3(SHOC2):c.519G>A (p.Met173Ile) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Uncertain Significance PS4 [Unmet], PS3 [Unmet], PM2 [MET] The c.519G>A (p.Met173Ile) variant in the SHOC2 gene has been observed in a proband with clinical features of a RASopathy (PS4 not met; GeneDx GTR Lab ID:26957 ClinVar SCV000209055.10). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Met173Ile variant may impact protein function (PS3 not met; PMID: 25137548). In summary, the clinical significance of the p.Met173Ile variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2. 25137548 RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA199174/MONDO:0021060/004 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 112915755 181766 G A NM_002834.4(PTPN11):c.1028G>A (p.Arg343Gln) 181766 CA297648 NM_002834.4:c.1028G>A, NC_000012.12:g.112477951G>A, CM000674.2:g.112477951G>A, NC_000012.11:g.112915755G>A, CM000674.1:g.112915755G>A, NC_000012.10:g.111400138G>A, NG_007459.1:g.64220G>A, LRG_614:g.64220G>A, NM_002834.3:c.1028G>A, LRG_614t1:c.1028G>A, NM_080601.1:c.1028G>A, XM_006719526.1:c.1028G>A, XM_006719527.1:c.914G>A, XM_011538613.1:c.1025G>A, NM_001330437.1:c.1028G>A, NM_080601.2:c.1028G>A, XM_011538613.2:c.1025G>A, XM_017019722.1:c.1025G>A, ENST00000351677.6:c.1028G>A, ENST00000392597.5:c.1028G>A, ENST00000635625.1:n.1028G>A, ENST00000635652.1:n.20G>A, NM_002834.4(PTPN11):c.1028G>A (p.Arg343Gln) PTPN11 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1028G>A (p.Arg343Gln) variant in the PTPN11 gene is 0.116% (27/16494) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA297648/MONDO:0021060/004 0.0507 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 89720876 183722 G A NM_000314.6(PTEN):c.1026+1G>A 183722 CA000103 NM_000314.6:c.1026+1G>A, NM_000314.5:c.1026+1G>A, NM_001304717.2:c.1545+1G>A, NM_001304718.1:c.435+1G>A, XM_006717926.2:c.981+1G>A, XM_011539981.1:c.1026+1G>A, XM_011539982.1:c.930+1G>A, XR_945791.1:n.1596+1G>A, NM_000314.7:c.1026+1G>A, NM_001304717.5:c.1545+1G>A, NM_001304718.2:c.435+1G>A, ENST00000371953.7:c.1026+1G>A, ENST00000472832.2:n.454G>A, NC_000010.11:g.87961119G>A, CM000672.2:g.87961119G>A, NC_000010.10:g.89720876G>A, CM000672.1:g.89720876G>A, NC_000010.9:g.89710856G>A, NG_007466.2:g.102681G>A, LRG_311:g.102681G>A, NM_000314.6(PTEN):c.1026+1G>A PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PVS1 [MET], PM2 [MET], PS4-Moderate [MET] PTEN c.1026+1G>A (IVS8+1G>A) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4) (PMID 28677221).PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28677221, internal laboratory contributor(s) SCV000212764.4) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000103/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68847213 184346 C T NM_004360.4(CDH1):c.1138-3C>T 184346 CA188674 NM_004360.4:c.1138-3C>T, NM_004360.3:c.1138-3C>T, LRG_301t1:c.1138-3C>T, XM_011523488.1:c.403-3C>T, XM_011523489.1:c.403-3C>T, NM_001317184.1:c.1137+1047C>T, NM_001317185.1:c.-478-3C>T, NM_001317186.1:c.-682-3C>T, ENST00000261769.9:c.1138-3C>T, ENST00000422392.6:c.1137+1047C>T, ENST00000562836.5:n.1209-3C>T, ENST00000565810.1:n.182-3C>T, ENST00000566510.5:c.982-3C>T, ENST00000566612.5:c.1138-3C>T, ENST00000611625.4:c.1138-3C>T, ENST00000612417.4:c.1138-3C>T, ENST00000621016.4:c.1138-3C>T, NC_000016.10:g.68813310C>T, CM000678.2:g.68813310C>T, NC_000016.9:g.68847213C>T, CM000678.1:g.68847213C>T, NC_000016.8:g.67404714C>T, NG_008021.1:g.81019C>T, LRG_301:g.81019C>T, NM_004360.4(CDH1):c.1138-3C>T CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Likely Benign BP7 [Unmet], BP5 [Unmet], BS1 [MET], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BA1 [Unmet], BP4 [MET], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.1138-3C>T variant has an allele frequency of 0.00121 (0.121%, 29/24,036 alleles) in the African subpopulation of the gnomAD cohort (BS1). There are at least 3 in silico predictors in agreement that this variant does not affect splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BP4. 15322508 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA188674/MONDO:0007648/007 0.3246 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89720690 184466 C G NM_000314.6(PTEN):c.841C>G (p.Pro281Ala) 184466 CA000211 NM_000314.6:c.841C>G, NM_000314.5:c.841C>G, NM_001304717.2:c.1360C>G, NM_001304718.1:c.250C>G, XM_006717926.2:c.796C>G, XM_011539981.1:c.841C>G, XM_011539982.1:c.745C>G, XR_945791.1:n.1411C>G, NM_000314.7:c.841C>G, NM_001304717.5:c.1360C>G, NM_001304718.2:c.250C>G, ENST00000371953.7:c.841C>G, ENST00000472832.2:n.268C>G, NC_000010.11:g.87960933C>G, CM000672.2:g.87960933C>G, NC_000010.10:g.89720690C>G, CM000672.1:g.89720690C>G, NC_000010.9:g.89710670C>G, NG_007466.2:g.102495C>G, LRG_311:g.102495C>G, NM_000314.6(PTEN):c.841C>G (p.Pro281Ala) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BA1 [Unmet], BS3-Supporting [MET], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] PTEN c.841C>G (p.Pro281Ala) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) 29785012, 29706350, 29945567 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000211/MONDO:0017623/003 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 89624301 184505 G A NM_000314.6(PTEN):c.75G>A (p.Leu25=) 184505 CA000197 NM_000314.6:c.75G>A, NM_000314.5:c.75G>A, NM_001304717.2:c.594G>A, NM_001304718.1:c.-631G>A, XM_006717926.2:c.75G>A, XM_011539981.1:c.75G>A, XR_945789.1:n.787G>A, XR_945790.1:n.787G>A, XR_945791.1:n.787G>A, NM_000314.7:c.75G>A, NM_001304717.5:c.594G>A, NM_001304718.2:c.-631G>A, ENST00000371953.7:c.75G>A, ENST00000462694.1:n.77G>A, ENST00000487939.1:n.96G>A, ENST00000610634.1:c.-28G>A, ENST00000618586.1:n.44G>A, NC_000010.11:g.87864544G>A, CM000672.2:g.87864544G>A, NC_000010.10:g.89624301G>A, CM000672.1:g.89624301G>A, NC_000010.9:g.89614281G>A, NG_007466.2:g.6106G>A, LRG_311:g.6106G>A, NG_033079.1:g.3894C>T, NM_000314.6(PTEN):c.75G>A (p.Leu25=) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], BP7 [MET], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.75G>A (p.Leu25=) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-12-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000197/MONDO:0017623/003 0.1877 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 89717675 184844 C T NM_000314.6(PTEN):c.700C>T (p.Arg234Trp) 184844 CA000183 NM_000314.6:c.700C>T, NM_000314.5:c.700C>T, NM_001304717.2:c.1219C>T, NM_001304718.1:c.109C>T, XM_006717926.2:c.655C>T, XM_011539981.1:c.700C>T, XM_011539982.1:c.604C>T, XR_945791.1:n.1270C>T, NM_000314.7:c.700C>T, NM_001304717.5:c.1219C>T, NM_001304718.2:c.109C>T, ENST00000371953.7:c.700C>T, ENST00000472832.2:n.127C>T, NC_000010.11:g.87957918C>T, CM000672.2:g.87957918C>T, NC_000010.10:g.89717675C>T, CM000672.1:g.89717675C>T, NC_000010.9:g.89707655C>T, NG_007466.2:g.99480C>T, LRG_311:g.99480C>T, NM_000314.6(PTEN):c.700C>T (p.Arg234Trp) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], BS2 [Unmet], BS3-Supporting [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet] PTEN c.700C>T (p.R234W) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) 30039884 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000183/MONDO:0017623/003 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 89717690 184878 A G NM_000314.6(PTEN):c.715A>G (p.Met239Val) 184878 CA000189 NM_000314.6:c.715A>G, NC_000010.11:g.87957933A>G, CM000672.2:g.87957933A>G, NC_000010.10:g.89717690A>G, CM000672.1:g.89717690A>G, NC_000010.9:g.89707670A>G, NG_007466.2:g.99495A>G, LRG_311:g.99495A>G, NM_000314.5:c.715A>G, NM_001304717.2:c.1234A>G, NM_001304718.1:c.124A>G, XM_006717926.2:c.670A>G, XM_011539981.1:c.715A>G, XM_011539982.1:c.619A>G, XR_945791.1:n.1285A>G, NM_000314.7:c.715A>G, NM_001304717.5:c.1234A>G, NM_001304718.2:c.124A>G, ENST00000371953.7:c.715A>G, ENST00000472832.2:n.142A>G, NM_000314.6(PTEN):c.715A>G (p.Met239Val) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP1 [Unmet], PP4 [Unmet], PP3 [Unmet], PP2 [MET], BP2 [Unmet], BP4 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet] PTEN c.715A>G (p.Met239Val) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000189/MONDO:0017623/003 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 10 89720813 185213 A T NM_000314.6(PTEN):c.964A>T (p.Lys322Ter) 185213 CA000235 NM_000314.6:c.964A>T, NC_000010.11:g.87961056A>T, CM000672.2:g.87961056A>T, NC_000010.10:g.89720813A>T, CM000672.1:g.89720813A>T, NC_000010.9:g.89710793A>T, NG_007466.2:g.102618A>T, LRG_311:g.102618A>T, NM_000314.5:c.964A>T, NM_001304717.2:c.1483A>T, NM_001304718.1:c.373A>T, XM_006717926.2:c.919A>T, XM_011539981.1:c.964A>T, XM_011539982.1:c.868A>T, XR_945791.1:n.1534A>T, NM_000314.7:c.964A>T, NM_001304717.5:c.1483A>T, NM_001304718.2:c.373A>T, ENST00000371953.7:c.964A>T, ENST00000472832.2:n.391A>T, NM_000314.6(PTEN):c.964A>T (p.Lys322Ter) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PVS1 [MET] PTEN c.964A>T (p.K322X) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000235/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89685275 185713 T G NM_000314.6(PTEN):c.170T>G (p.Leu57Trp) 185713 CA000131 NM_000314.6:c.170T>G, NM_000314.5:c.170T>G, NM_001304717.2:c.689T>G, NM_001304718.1:c.-541-5528T>G, XM_006717926.2:c.165-5528T>G, XM_011539981.1:c.170T>G, XM_011539982.1:c.74T>G, XR_945789.1:n.882T>G, XR_945790.1:n.882T>G, XR_945791.1:n.882T>G, NM_000314.7:c.170T>G, NM_001304717.5:c.689T>G, NM_001304718.2:c.-541-5528T>G, ENST00000371953.7:c.170T>G, ENST00000610634.1:c.68T>G, NC_000010.11:g.87925518T>G, CM000672.2:g.87925518T>G, NC_000010.10:g.89685275T>G, CM000672.1:g.89685275T>G, NC_000010.9:g.89675255T>G, NG_007466.2:g.67080T>G, LRG_311:g.67080T>G, NM_000314.6(PTEN):c.170T>G (p.Leu57Trp) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [MET], PS4 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.170T>G (p.L57W) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 9256433).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000131/MONDO:0017623/003 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89685317 185989 A T NM_000314.6(PTEN):c.209+3A>T 185989 CA000135 NM_000314.6:c.209+3A>T, NC_000010.11:g.87925560A>T, CM000672.2:g.87925560A>T, NC_000010.10:g.89685317A>T, CM000672.1:g.89685317A>T, NC_000010.9:g.89675297A>T, NG_007466.2:g.67122A>T, LRG_311:g.67122A>T, NM_000314.5:c.209+3A>T, NM_001304717.2:c.728+3A>T, NM_001304718.1:c.-541-5486A>T, XM_006717926.2:c.165-5486A>T, XM_011539981.1:c.209+3A>T, XM_011539982.1:c.113+3A>T, XR_945789.1:n.921+3A>T, XR_945790.1:n.921+3A>T, XR_945791.1:n.921+3A>T, NM_000314.7:c.209+3A>T, NM_001304717.5:c.728+3A>T, NM_001304718.2:c.-541-5486A>T, ENST00000371953.7:c.209+3A>T, ENST00000498703.1:n.35+3A>T, ENST00000610634.1:c.107+3A>T, NM_000314.6(PTEN):c.209+3A>T PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PP3 [MET] PTEN c.209+3A>T (IVS3+3A>T) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP3: At least 2 out of 3 in silico models predict a splicing impact. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-11-08 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000135/MONDO:0017623/003 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692880 186161 A G NM_000314.6(PTEN):c.364A>G (p.Ile122Val) 186161 CA000147 NM_000314.6:c.364A>G, NC_000010.11:g.87933123A>G, CM000672.2:g.87933123A>G, NC_000010.10:g.89692880A>G, CM000672.1:g.89692880A>G, NC_000010.9:g.89682860A>G, NG_007466.2:g.74685A>G, LRG_311:g.74685A>G, NM_000314.5:c.364A>G, NM_001304717.2:c.883A>G, NM_001304718.1:c.-387A>G, XM_006717926.2:c.319A>G, XM_011539981.1:c.364A>G, XM_011539982.1:c.268A>G, XR_945789.1:n.1076A>G, XR_945790.1:n.1076A>G, XR_945791.1:n.1076A>G, NM_000314.7:c.364A>G, NM_001304717.5:c.883A>G, NM_001304718.2:c.-387A>G, ENST00000371953.7:c.364A>G, ENST00000498703.1:n.190A>G, ENST00000610634.1:c.262A>G, NM_000314.6(PTEN):c.364A>G (p.Ile122Val) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PVS1 [Unmet], PM6 [Unmet], PM2 [MET], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], BS3 [MET], BS4 [Unmet], BS1 [Unmet], BP7 [Unmet], BP5 [Unmet] PTEN c.364A>G (p.Ile122Val) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 21828076, 29706350, 29785012) 21828076, 29785012, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000147/MONDO:0017623/003 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 89692820 186427 A C NM_000314.6(PTEN):c.304A>C (p.Lys102Gln) 186427 CA000139 NM_000314.6:c.304A>C, NC_000010.11:g.87933063A>C, CM000672.2:g.87933063A>C, NC_000010.10:g.89692820A>C, CM000672.1:g.89692820A>C, NC_000010.9:g.89682800A>C, NG_007466.2:g.74625A>C, LRG_311:g.74625A>C, NM_000314.5:c.304A>C, NM_001304717.2:c.823A>C, NM_001304718.1:c.-447A>C, XM_006717926.2:c.259A>C, XM_011539981.1:c.304A>C, XM_011539982.1:c.208A>C, XR_945789.1:n.1016A>C, XR_945790.1:n.1016A>C, XR_945791.1:n.1016A>C, NM_000314.7:c.304A>C, NM_001304717.5:c.823A>C, NM_001304718.2:c.-447A>C, ENST00000371953.7:c.304A>C, ENST00000498703.1:n.130A>C, ENST00000610634.1:c.202A>C, NM_000314.6(PTEN):c.304A>C (p.Lys102Gln) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [MET], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] PTEN c.304A>C (p.Lys102Gln) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000139/MONDO:0017623/003 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 16 68863687 187464 AT A NM_004360.4(CDH1):c.2430delT (p.Phe810Leufs) 187464 CA197715 NM_004360.4:c.2430delT, NC_000016.10:g.68829788del, CM000678.2:g.68829788del, NC_000016.9:g.68863691del, CM000678.1:g.68863691del, NC_000016.8:g.67421192del, NG_008021.1:g.97497del, LRG_301:g.97497del, NM_004360.3:c.2430del, LRG_301t1:c.2430del, XM_011523488.1:c.1695del, XM_011523489.1:c.1695del, NM_001317184.1:c.2247del, NM_001317185.1:c.882del, NM_001317186.1:c.465del, NM_004360.4:c.2430del, ENST00000261769.9:c.2430del, ENST00000422392.6:c.2247del, ENST00000562118.1:n.648del, ENST00000562836.5:n.2501del, ENST00000566510.5:c.*1096del, ENST00000566612.5:c.*670del, ENST00000611625.4:c.2493del, ENST00000612417.4:c.1853+3234del, ENST00000621016.4:c.1866-4415del, NM_004360.4(CDH1):c.2430delT (p.Phe810Leufs) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BS1 [Unmet], BS4 [Unmet], BP5 [Unmet], BP7 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP1 [Unmet], PP3 [Unmet], PVS1-Strong [MET], PM4 [Unmet], BP2 [Unmet], BP4 [Unmet], BA1 [Unmet], PS2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [MET] The c.2430delT (p.Phe810Leufs*6) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 26182300, SCV000261293.4, SCV000218032.4). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Strong, PM2, PS4. 26182300 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA197715/MONDO:0007648/007 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89685269 187590 G A NM_000314.6(PTEN):c.165-1G>A 187590 CA000129 NM_000314.6:c.165-1G>A, NM_000314.5:c.165-1G>A, NM_001304717.2:c.684-1G>A, NM_001304718.1:c.-541-5534G>A, XM_006717926.2:c.165-5534G>A, XM_011539981.1:c.165-1G>A, XM_011539982.1:c.69-1G>A, XR_945789.1:n.877-1G>A, XR_945790.1:n.877-1G>A, XR_945791.1:n.877-1G>A, NM_000314.7:c.165-1G>A, NM_001304717.5:c.684-1G>A, NM_001304718.2:c.-541-5534G>A, ENST00000371953.7:c.165-1G>A, ENST00000610634.1:c.63-1G>A, NC_000010.11:g.87925512G>A, CM000672.2:g.87925512G>A, NC_000010.10:g.89685269G>A, CM000672.1:g.89685269G>A, NC_000010.9:g.89675249G>A, NG_007466.2:g.67074G>A, LRG_311:g.67074G>A, NM_000314.6(PTEN):c.165-1G>A PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PVS1 [MET], PM2 [MET] PTEN c.165-1G>A (IVS2-1G>A) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000129/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89720741 187657 C T NM_000314.6(PTEN):c.892C>T (p.Gln298Ter) 187657 CA000219 NM_000314.6:c.892C>T, NC_000010.11:g.87960984C>T, CM000672.2:g.87960984C>T, NC_000010.10:g.89720741C>T, CM000672.1:g.89720741C>T, NC_000010.9:g.89710721C>T, NG_007466.2:g.102546C>T, LRG_311:g.102546C>T, NM_000314.5:c.892C>T, NM_001304717.2:c.1411C>T, NM_001304718.1:c.301C>T, XM_006717926.2:c.847C>T, XM_011539981.1:c.892C>T, XM_011539982.1:c.796C>T, XR_945791.1:n.1462C>T, NM_000314.7:c.892C>T, NM_001304717.5:c.1411C>T, NM_001304718.2:c.301C>T, ENST00000371953.7:c.892C>T, ENST00000472832.2:n.319C>T, NM_000314.6(PTEN):c.892C>T (p.Gln298Ter) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PVS1 [MET], PM2 [MET], PS4-Supporting [MET] PTEN c.892C>T (p.Q298X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23470840) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000219/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89725188 187673 C T NM_000314.6(PTEN):c.1171C>T (p.Pro391Ser) 187673 CA000118 NM_000314.6:c.1171C>T, NM_000314.5:c.1171C>T, NM_001304717.2:c.1690C>T, NM_001304718.1:c.580C>T, XM_006717926.2:c.1126C>T, XM_011539982.1:c.1075C>T, XR_945791.1:n.1741C>T, NM_000314.7:c.1171C>T, NM_001304717.5:c.1690C>T, NM_001304718.2:c.580C>T, ENST00000371953.7:c.1171C>T, NC_000010.11:g.87965431C>T, CM000672.2:g.87965431C>T, NC_000010.10:g.89725188C>T, CM000672.1:g.89725188C>T, NC_000010.9:g.89715168C>T, NG_007466.2:g.106993C>T, LRG_311:g.106993C>T, NM_000314.6(PTEN):c.1171C>T (p.Pro391Ser) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PP2 [MET] PTEN c.1171C>T (p.P391S) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-11-08 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000118/MONDO:0017623/003 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 89711927 187827 T C NM_000314.6(PTEN):c.545T>C (p.Leu182Ser) 187827 CA000177 NM_000314.6:c.545T>C, NC_000010.11:g.87952170T>C, CM000672.2:g.87952170T>C, NC_000010.10:g.89711927T>C, CM000672.1:g.89711927T>C, NC_000010.9:g.89701907T>C, NG_007466.2:g.93732T>C, LRG_311:g.93732T>C, NM_000314.5:c.545T>C, NM_001304717.2:c.1064T>C, NM_001304718.1:c.-47T>C, XM_006717926.2:c.500T>C, XM_011539981.1:c.545T>C, XM_011539982.1:c.449T>C, XR_945789.1:n.1416T>C, XR_945790.1:n.1533T>C, XR_945791.1:n.1205-5683T>C, NM_000314.7:c.545T>C, NM_001304717.5:c.1064T>C, NM_001304718.2:c.-47T>C, ENST00000371953.7:c.545T>C, NM_000314.6(PTEN):c.545T>C (p.Leu182Ser) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] PTEN c.545T>C (p.Leu182Ser) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). Of note, this variant may be disease-causing when present in the homozygous state (PMID 26443266), but this expert panel curation is based on presence in the heterozygous state. PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 28097321, 21194675, 26443266 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000177/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 7 107312637 189148 C CT NM_000441.1(SLC26A4):c.365dupT (p.Ile124Tyrfs) 189148 CA274422 NM_000441.1:c.365dupT, NM_000441.1:c.365dup, XM_005250425.1:c.365dup, XM_006716025.2:c.365dup, XM_005250425.2:c.365dup, XM_006716025.3:c.365dup, XM_017012318.1:c.365dup, ENST00000265715.7:c.365dup, ENST00000440056.1:c.365dup, NC_000007.14:g.107672198dup, CM000669.2:g.107672198dup, NC_000007.13:g.107312643dup, CM000669.1:g.107312643dup, NC_000007.12:g.107099879dup, NG_008489.1:g.16564dup, NM_000441.1(SLC26A4):c.365dupT (p.Ile124Tyrfs) SLC26A4 Pendred syndrome MONDO:0010134 Autosomal recessive inheritance Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], PP3 [Unmet], PP4 [MET], PP1 [Unmet], BS2 [Unmet], BP3 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], PM3-Supporting [MET], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The p.Ile124Tyrfs variant in SLC26A4 is predicted to cause a premature stop codon in biologically-relevant-exon 4/21 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). The allele frequency of the p.Ile124fs variant is in 0.003% (1/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). At least one patient with the variant displayed features of enlarged vestibular aqueduct and Mondini malformation which are consistent with Pendred syndrome (PP4; PMID:15679828). This variant has been detected in 2 patients with hearing loss in trans with suspected pathogenic variants (PM3_P, PMID:15679828). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_P. 15679828, 15679828, 15679828 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA274422/MONDO:0010134/005 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692800 189403 C T NM_000314.6(PTEN):c.284C>T (p.Pro95Leu) 189403 CA000383 NM_000314.6:c.284C>T, NM_000314.5:c.284C>T, NM_001304717.2:c.803C>T, NM_001304718.1:c.-467C>T, XM_006717926.2:c.239C>T, XM_011539981.1:c.284C>T, XM_011539982.1:c.188C>T, XR_945789.1:n.996C>T, XR_945790.1:n.996C>T, XR_945791.1:n.996C>T, NM_000314.7:c.284C>T, NM_001304717.5:c.803C>T, NM_001304718.2:c.-467C>T, ENST00000371953.7:c.284C>T, ENST00000498703.1:n.110C>T, ENST00000610634.1:c.182C>T, NC_000010.11:g.87933043C>T, CM000672.2:g.87933043C>T, NC_000010.10:g.89692800C>T, CM000672.1:g.89692800C>T, NC_000010.9:g.89682780C>T, NG_007466.2:g.74605C>T, LRG_311:g.74605C>T, NM_000314.6(PTEN):c.284C>T (p.Pro95Leu) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PM6 [MET], PVS1 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], PS4-Supporting [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [MET], PS2 [Unmet], PS1 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet] PTEN c.284C>T (p.Pro95Leu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 21828076, PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor ClinVar Organization ID 26957) 25669429, 21659347, 28526761, 21194675, 20600018, 21828076, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA000383/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 5 Likely Pathogenic 10 89692923 189406 G A NM_000314.6(PTEN):c.407G>A (p.Cys136Tyr) 189406 CA000451 NM_000314.6:c.407G>A, NC_000010.11:g.87933166G>A, CM000672.2:g.87933166G>A, NC_000010.10:g.89692923G>A, CM000672.1:g.89692923G>A, NC_000010.9:g.89682903G>A, NG_007466.2:g.74728G>A, LRG_311:g.74728G>A, NM_000314.5:c.407G>A, NM_001304717.2:c.926G>A, NM_001304718.1:c.-344G>A, XM_006717926.2:c.362G>A, XM_011539981.1:c.407G>A, XM_011539982.1:c.311G>A, XR_945789.1:n.1119G>A, XR_945790.1:n.1119G>A, XR_945791.1:n.1119G>A, NM_000314.7:c.407G>A, NM_001304717.5:c.926G>A, NM_001304718.2:c.-344G>A, ENST00000371953.7:c.407G>A, ENST00000498703.1:n.233G>A, ENST00000610634.1:c.305G>A, NM_000314.6(PTEN):c.407G>A (p.Cys136Tyr) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PP2 [MET], PS4-Supporting [MET], PS2 [MET], PS3 [MET] PTEN c.407G>A (p.C136Y) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000222113.9)PS3: Phosphatase activity <50% of wild-type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 10866302)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Probands with specificity score of 1-1.5. (PMID 9735393, internal laboratory contributor(s) SCV000222113.9) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000451/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 5 Likely Pathogenic 10 89711893 189411 C T NM_000314.6(PTEN):c.511C>T (p.Gln171Ter) 189411 CA000494 NM_000314.6:c.511C>T, NM_000314.5:c.511C>T, NM_001304717.2:c.1030C>T, NM_001304718.1:c.-81C>T, XM_006717926.2:c.466C>T, XM_011539981.1:c.511C>T, XM_011539982.1:c.415C>T, XR_945789.1:n.1382C>T, XR_945790.1:n.1499C>T, XR_945791.1:n.1205-5717C>T, NM_000314.7:c.511C>T, NM_001304717.5:c.1030C>T, NM_001304718.2:c.-81C>T, ENST00000371953.7:c.511C>T, NC_000010.11:g.87952136C>T, CM000672.2:g.87952136C>T, NC_000010.10:g.89711893C>T, CM000672.1:g.89711893C>T, NC_000010.9:g.89701873C>T, NG_007466.2:g.93698C>T, LRG_311:g.93698C>T, NM_000314.6(PTEN):c.511C>T (p.Gln171Ter) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PVS1 [MET], PM2 [MET], PM6 [MET], PS4-Moderate [MET] PTEN c.511C>T (p.Q171X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 22595938)PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 17043057, PMID 22595938) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000494/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89725230 189424 AT A NM_000314.6(PTEN):c.*10delT 189424 CA000290 NM_000314.6:c.*10delT, NC_000010.11:g.87965482del, CM000672.2:g.87965482del, NC_000010.10:g.89725239del, CM000672.1:g.89725239del, NC_000010.9:g.89715219del, NG_007466.2:g.107044del, LRG_311:g.107044del, NM_000314.5:c.*10del, NM_000314.6:c.*10del, NM_001304717.2:c.*10del, NM_001304718.1:c.*10del, XM_006717926.2:c.*10del, XM_011539982.1:c.*10del, XR_945791.1:n.1792del, NM_000314.7:c.*10del, NM_001304717.5:c.*10del, NM_001304718.2:c.*10del, ENST00000371953.7:c.*10del, NM_000314.6(PTEN):c.*10delT PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET] PTEN c.*10delT (NC_000010.10:g.89725239delT) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-04-06 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000290/MONDO:0017623/003 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 10 89692876 189426 A C NM_000314.6(PTEN):c.360A>C (p.Ala120=) 189426 CA000412 NM_000314.6:c.360A>C, NC_000010.11:g.87933119A>C, CM000672.2:g.87933119A>C, NC_000010.10:g.89692876A>C, CM000672.1:g.89692876A>C, NC_000010.9:g.89682856A>C, NG_007466.2:g.74681A>C, LRG_311:g.74681A>C, NM_000314.5:c.360A>C, NM_001304717.2:c.879A>C, NM_001304718.1:c.-391A>C, XM_006717926.2:c.315A>C, XM_011539981.1:c.360A>C, XM_011539982.1:c.264A>C, XR_945789.1:n.1072A>C, XR_945790.1:n.1072A>C, XR_945791.1:n.1072A>C, NM_000314.7:c.360A>C, NM_001304717.5:c.879A>C, NM_001304718.2:c.-391A>C, ENST00000371953.7:c.360A>C, ENST00000498703.1:n.186A>C, ENST00000610634.1:c.258A>C, NM_000314.6(PTEN):c.360A>C (p.Ala120=) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign BP4 [MET], BP7 [MET] PTEN c.360A>C (p.A120=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-12-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000412/MONDO:0017623/003 0.1 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 89623026 189433 TGCAAAAGCCGCA T NM_000314.6(PTEN):c.-1195_-1184delAAGCCGCAGCAA 189433 CA163819 NC_000010.11:g.87863274_87863285del, CM000672.2:g.87863274_87863285del, NC_000010.10:g.89623031_89623042del, CM000672.1:g.89623031_89623042del, NC_000010.9:g.89613011_89613022del, NG_007466.2:g.4837_4848del, LRG_311:g.4837_4848del, NG_033079.1:g.5157_5168del, NM_001126049.1:c.-794_-783del, ENST00000371953.7:c.-1196_-1185del, ENST00000445946.3:c.-794_-783del, NM_000314.6(PTEN):c.-1195_-1184delAAGCCGCAGCAA KLLN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BP7 [Unmet], BP5 [MET], BS1 [Unmet], BS3 [Unmet], BS4-Supporting [MET] PTEN c.-1195del12 (NC_000010.10:g.89623031_89623042delAAGCCGCAGCAA) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS4_P: Lack of segregation in affected members of one family. (Internal laboratory contributor SCV SCV000222146.7)BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributors SCV000222146.7, SCV000183826.5) 21194675, 28821472, 21532617, 28495237, 25669429, 28157521, 21532617, 21532617 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA163819/MONDO:0017623/003 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89720832 189441 CAAAT C NM_000314.6(PTEN):c.987_990delTAAA (p.Asn329Lysfs) 189441 CA000656 NM_000314.6:c.987_990delTAAA, NM_000314.5:c.987_990del, NM_000314.6:c.987_990del, NM_001304717.2:c.1506_1509del, NM_001304718.1:c.396_399del, XM_006717926.2:c.942_945del, XM_011539981.1:c.987_990del, XM_011539982.1:c.891_894del, XR_945791.1:n.1557_1560del, NM_000314.7:c.987_990del, NM_001304717.5:c.1506_1509del, NM_001304718.2:c.396_399del, ENST00000371953.7:c.987_990del, ENST00000472832.2:n.414_417del, NC_000010.11:g.87961079_87961082del, CM000672.2:g.87961079_87961082del, NC_000010.10:g.89720836_89720839del, CM000672.1:g.89720836_89720839del, NC_000010.9:g.89710816_89710819del, NG_007466.2:g.102641_102644del, LRG_311:g.102641_102644del, NM_000314.6(PTEN):c.987_990delTAAA (p.Asn329Lysfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PVS1 [MET], PM2 [MET], PS4-Supporting [MET] PTEN c.987_990delTAAA (p.N329KfsX14) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 10232405) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000656/MONDO:0017623/003 0.9971 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89653781 189462 G C NM_000314.6(PTEN):c.80-1G>C 189462 CA000586 NM_000314.6:c.80-1G>C, NC_000010.11:g.87894024G>C, CM000672.2:g.87894024G>C, NC_000010.10:g.89653781G>C, CM000672.1:g.89653781G>C, NC_000010.9:g.89643761G>C, NG_007466.2:g.35586G>C, LRG_311:g.35586G>C, NM_000314.5:c.80-1G>C, NM_001304717.2:c.599-1G>C, NM_001304718.1:c.-626-1G>C, XM_006717926.2:c.80-1G>C, XM_011539981.1:c.80-1G>C, XM_011539982.1:c.68+13586G>C, XR_945789.1:n.792-1G>C, XR_945790.1:n.792-1G>C, XR_945791.1:n.792-1G>C, NM_000314.7:c.80-1G>C, NM_001304717.5:c.599-1G>C, NM_001304718.2:c.-626-1G>C, ENST00000371953.7:c.80-1G>C, ENST00000462694.1:n.82-1G>C, ENST00000610634.1:c.-23-1G>C, NM_000314.6(PTEN):c.80-1G>C PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PVS1 [MET] PTEN c.80-1G>C (IVS1-1G>C) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000586/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89711899 189500 C T NM_000314.6(PTEN):c.517C>T (p.Arg173Cys) 189500 CA000498 NM_000314.6:c.517C>T, NC_000010.11:g.87952142C>T, CM000672.2:g.87952142C>T, NC_000010.10:g.89711899C>T, CM000672.1:g.89711899C>T, NC_000010.9:g.89701879C>T, NG_007466.2:g.93704C>T, LRG_311:g.93704C>T, NM_000314.5:c.517C>T, NM_001304717.2:c.1036C>T, NM_001304718.1:c.-75C>T, XM_006717926.2:c.472C>T, XM_011539981.1:c.517C>T, XM_011539982.1:c.421C>T, XR_945789.1:n.1388C>T, XR_945790.1:n.1505C>T, XR_945791.1:n.1205-5711C>T, NM_000314.7:c.517C>T, NM_001304717.5:c.1036C>T, NM_001304718.2:c.-75C>T, ENST00000371953.7:c.517C>T, NM_000314.6(PTEN):c.517C>T (p.Arg173Cys) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PS2-Very Strong [MET], PM2 [MET], PP1 [MET], PP2 [MET], PS3 [MET], PS4-Moderate [MET] PTEN c.517C>T (p.R173C) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 17526800, PMID 22628360, internal laboratory contributor(s) SCV000222220.10)PS3: Phosphatase activity <50% of wild type. (PMID 10866302)PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 22628360, PMID 17526800, PMID 17526801)PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 22628360)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA000498/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 5 Likely Pathogenic 10 89623167 189520 C G NM_000314.6(PTEN):c.-1059C>G 189520 CA300594 NM_000314.6:c.-1059C>G, NC_000010.11:g.87863410C>G, CM000672.2:g.87863410C>G, NC_000010.10:g.89623167C>G, CM000672.1:g.89623167C>G, NC_000010.9:g.89613147C>G, NG_007466.2:g.4973C>G, LRG_311:g.4973C>G, NG_033079.1:g.5028G>C, NM_001126049.1:c.-923G>C, ENST00000371953.7:c.-1060C>G, ENST00000445946.3:c.-923G>C, NM_000314.6(PTEN):c.-1059C>G KLLN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Benign BA1 [MET] PTEN c.-1059C>G (NC_000010.10:g.89623167C>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.0138 (1.38%, 120/8698 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA300594/MONDO:0017623/003 0.025 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 1 216040521 197510 T C NM_206933.2(USH2A):c.8682-9A>G 197510 CA275277 NM_206933.2:c.8682-9A>G, NC_000001.11:g.215867179T>C, CM000663.2:g.215867179T>C, NC_000001.10:g.216040521T>C, CM000663.1:g.216040521T>C, NC_000001.9:g.214107144T>C, NG_009497.1:g.561218A>G, NM_206933.3:c.8682-9A>G, ENST00000307340.7:c.8682-9A>G, NM_206933.2(USH2A):c.8682-9A>G USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Pathogenic PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP1 [Unmet], PP4 [MET], PP3 [MET], PM3-Very Strong [MET], PM2-Supporting [MET], BP2 [Unmet], BP4 [Unmet], BP3 [Unmet], BA1 [Unmet], PS4 [Unmet], PS2 [Unmet], PS3 [Unmet], PM1 [Unmet], PM4 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The c.8682-9A>G variant in USH2A has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 27318125, 25425308, 28944237, 23591405). The allele frequency of the c.8682-9A>G variant in the USH2A gene is 0.04% (5/10112) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). At least one patient with this variant displayed features of retinitis pigmentosa and hearing loss which is consistent with Usher syndrome (PP4; PMID: 27318125, 25425308, 28944237, 23591405). Computational prediction tools and conservation analysis suggest that the c.8682-9A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PM2_Supporting, PP4, PP3. 25425308, 28944237, 23591405, 27318125, 25425308, 28944237, 23591405, 27318125, 18273898, 27318125 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-24 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA275277/MONDO:0019501/005 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 2 39281777 197778 T C NM_005633.3(SOS1):c.698A>G (p.Asn233Ser) 197778 CA246107 NM_005633.3:c.698A>G, NC_000002.12:g.39054636T>C, CM000664.2:g.39054636T>C, NC_000002.11:g.39281777T>C, CM000664.1:g.39281777T>C, NC_000002.10:g.39135281T>C, NG_007530.1:g.70828A>G, LRG_754:g.70828A>G, LRG_754t1:c.698A>G, XM_005264515.3:c.698A>G, XM_011533060.1:c.791A>G, XM_011533061.1:c.791A>G, XM_011533062.1:c.677A>G, XM_011533063.1:c.674A>G, XM_011533064.1:c.527A>G, XM_011533065.1:c.791A>G, XM_005264515.4:c.698A>G, XM_011533062.2:c.677A>G, XM_011533064.2:c.527A>G, ENST00000395038.6:c.698A>G, ENST00000402219.6:c.698A>G, ENST00000426016.5:c.698A>G, NM_005633.3(SOS1):c.698A>G (p.Asn233Ser) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.698A>G (p.Asn233Ser) variant in the SOS1 gene is 0.0393% (8/10108) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA246107/MONDO:0021060/004 0.025 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 1 215822033 198366 C T NM_206933.2(USH2A):c.14419G>A (p.Ala4807Thr) 198366 CA246980 NM_206933.2:c.14419G>A, NC_000001.11:g.215648691C>T, CM000663.2:g.215648691C>T, NC_000001.10:g.215822033C>T, CM000663.1:g.215822033C>T, NC_000001.9:g.213888656C>T, NG_009497.1:g.779706G>A, NM_206933.3:c.14419G>A, ENST00000307340.7:c.14419G>A, NM_206933.2(USH2A):c.14419G>A (p.Ala4807Thr) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Uncertain Significance PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], PM2-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] The c.14419G>A (p.Ala4807Thr) variant in USH2A has been observed in at least one individual with hearing loss (Partners LMM ClinVar SCV000272892.2; PS4 not met). The variant has been observed in 0.01% (5/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA246980/MONDO:0019501/005 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103310907 203873 A G NM_000277.1(PAH):c.2T>C (p.Met1Thr) 203873 CA312807 NM_000277.1:c.2T>C, XM_011538422.1:c.2T>C, NM_000277.2:c.2T>C, NM_001354304.1:c.2T>C, XM_017019370.2:c.2T>C, NM_000277.3:c.2T>C, ENST00000307000.7:c.-146T>C, ENST00000546844.1:c.2T>C, ENST00000547319.1:n.313T>C, ENST00000549111.5:n.98T>C, ENST00000551337.5:c.2T>C, ENST00000551988.5:n.91T>C, ENST00000553106.5:c.2T>C, ENST00000635500.1:n.29-4231T>C, NC_000012.12:g.102917129A>G, CM000674.2:g.102917129A>G, NC_000012.11:g.103310907A>G, CM000674.1:g.103310907A>G, NC_000012.10:g.101835037A>G, NG_008690.1:g.5474T>C, NG_008690.2:g.46282T>C, NM_000277.1(PAH):c.2T>C (p.Met1Thr) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PVS1 [MET], PP4 [Unmet] c.2T>C (p.Met1Thr) is a null PAH variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant has an extremely low frequency in ExAC, ESP, gnomAD. However, it has not been reported in the literature to our knowledge. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA312807/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103288623 208180 G T NM_000277.2(PAH):c.242C>A (p.Thr81Asn) 208180 CA275937 NM_000277.2:c.242C>A, NC_000012.12:g.102894845G>T, CM000674.2:g.102894845G>T, NC_000012.11:g.103288623G>T, CM000674.1:g.103288623G>T, NC_000012.10:g.101812753G>T, NG_008690.1:g.27758C>A, NG_008690.2:g.68566C>A, NM_000277.1:c.242C>A, XM_011538422.1:c.242C>A, NM_001354304.1:c.242C>A, XM_017019370.2:c.242C>A, NM_000277.3:c.242C>A, ENST00000307000.7:c.227C>A, ENST00000546844.1:c.242C>A, ENST00000548677.2:n.329C>A, ENST00000548928.1:n.164C>A, ENST00000549111.5:n.338C>A, ENST00000550978.6:n.226C>A, ENST00000551337.5:c.242C>A, ENST00000551988.5:n.331C>A, ENST00000553106.5:c.242C>A, NM_000277.2(PAH):c.242C>A (p.Thr81Asn) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET] The c.242C>A (p.Thr81Asn) variant in PAH is reported in 1 PKU patient. PAH and BH4DH genes were sequenced. It was detected with p.V230I which is interpreted as Pathogenic/Likely Pathogenic in ClinVar. (PMID: 23942198) This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, MutationTaster, and Polyphen-2. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3. 23942198, 23942198 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA275937/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103245482 208182 A G NM_000277.2(PAH):c.895T>C (p.Phe299Leu) 208182 CA275941 NM_000277.2:c.895T>C, NC_000012.12:g.102851704A>G, CM000674.2:g.102851704A>G, NC_000012.11:g.103245482A>G, CM000674.1:g.103245482A>G, NC_000012.10:g.101769612A>G, NG_008690.1:g.70899T>C, NG_008690.2:g.111707T>C, NM_000277.1:c.895T>C, XM_011538422.1:c.895T>C, NM_001354304.1:c.895T>C, NM_000277.3:c.895T>C, ENST00000307000.7:c.880T>C, ENST00000549247.6:n.654T>C, ENST00000551114.2:n.557T>C, ENST00000553106.5:c.895T>C, ENST00000635477.1:n.56T>C, NM_000277.2(PAH):c.895T>C (p.Phe299Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [MET], PP3 [MET] The c.895T>C (p.Phe299Leu) variant in PAH is reported as Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 208182); no further information is provided. At the time of review (5/25/19), the variant does not appear to be reported in the published literature and/or in the BioPKU database. The variant results in the substitution of a highly conserved Phenylalanine residue with Leucine; the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., predicted deleterious in SIFT, Polyphen2, Mutation Taster; REVEL= 0.96) (PP3). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Another missense variant at this site, p.Phe299Cys, has been previously reported Pathogenic/Likely Pathogenic by seven submitters in ClinVar (variant ID 613), where it was noted to be a recurrent allele among Norwegian PKU patients and have in-vitro data supporting that it impaired protein function. Another missense variant at this site, Phe299Ser, has also been reported in the BioPKU database (PAH0800). These reports of those variants support use of PM5. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA275941/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36231827 212089 A T NM_001754.4(RUNX1):c.557T>A (p.Val186Asp) 212089 CA248819 NM_001754.4:c.557T>A, NC_000021.9:g.34859530A>T, CM000683.2:g.34859530A>T, NC_000021.8:g.36231827A>T, CM000683.1:g.36231827A>T, NC_000021.7:g.35153697A>T, NG_011402.2:g.1130182T>A, LRG_482:g.1130182T>A, NM_001001890.2:c.476T>A, NM_001122607.1:c.476T>A, LRG_482t1:c.557T>A, XM_005261068.3:c.521T>A, XM_005261069.3:c.557T>A, XM_011529766.1:c.557T>A, XM_011529767.1:c.518T>A, XM_011529768.1:c.518T>A, XM_011529770.1:c.557T>A, XR_937576.1:n.736T>A, XM_005261069.4:c.557T>A, XM_011529766.2:c.557T>A, XM_011529767.2:c.518T>A, XM_011529768.2:c.518T>A, XM_011529770.2:c.557T>A, XM_017028487.1:c.404T>A, XR_937576.2:n.783T>A, ENST00000300305.7:c.557T>A, ENST00000344691.8:c.476T>A, ENST00000358356.9:c.476T>A, ENST00000399237.6:c.521T>A, ENST00000399240.5:c.476T>A, ENST00000437180.5:c.557T>A, ENST00000467577.1:n.49T>A, ENST00000482318.5:c.*147T>A, NM_001754.4(RUNX1):c.557T>A (p.Val186Asp) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1-Supporting [MET], PS3 [Unmet], PS1 [Unmet], PS4 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [MET], PP1 [Unmet], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.557T>A (p.Val186Asp) missense variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It has a REVEL score >0.75 (0.953) (PP3). This variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2, PP3, PM1_Supporting. 28104920 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA248819/MONDO:0011071/008 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 10 89711903 220007 A G NM_000314.6(PTEN):c.521A>G (p.Tyr174Cys) 220007 CA349032 NM_000314.6:c.521A>G, NC_000010.11:g.87952146A>G, CM000672.2:g.87952146A>G, NC_000010.10:g.89711903A>G, CM000672.1:g.89711903A>G, NC_000010.9:g.89701883A>G, NG_007466.2:g.93708A>G, LRG_311:g.93708A>G, NM_000314.5:c.521A>G, NM_001304717.2:c.1040A>G, NM_001304718.1:c.-71A>G, XM_006717926.2:c.476A>G, XM_011539981.1:c.521A>G, XM_011539982.1:c.425A>G, XR_945789.1:n.1392A>G, XR_945790.1:n.1509A>G, XR_945791.1:n.1205-5707A>G, NM_000314.7:c.521A>G, NM_001304717.5:c.1040A>G, NM_001304718.2:c.-71A>G, ENST00000371953.7:c.521A>G, NM_000314.6(PTEN):c.521A>G (p.Tyr174Cys) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PP2 [MET], PS4-Supporting [MET], PS2 [MET] PTEN c.521A>G (p.Y174C) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000602123.1)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor(s) SCV000602123.1) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-09-26 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA349032/MONDO:0017623/003 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68835695 220611 A G NM_004360.4(CDH1):c.286A>G (p.Ile96Val) 220611 CA349520 NM_004360.4:c.286A>G, NM_004360.3:c.286A>G, LRG_301t1:c.286A>G, XM_011523488.1:c.-450A>G, XM_011523489.1:c.-450A>G, NM_001317184.1:c.286A>G, NM_001317185.1:c.-1330A>G, NM_001317186.1:c.-1534A>G, ENST00000261769.9:c.286A>G, ENST00000422392.6:c.286A>G, ENST00000561751.1:n.53A>G, ENST00000562836.5:n.357A>G, ENST00000564676.5:n.568A>G, ENST00000564745.1:n.281A>G, ENST00000566510.5:c.286A>G, ENST00000566612.5:c.286A>G, ENST00000611625.4:c.286A>G, ENST00000612417.4:c.286A>G, ENST00000621016.4:c.286A>G, NC_000016.10:g.68801792A>G, CM000678.2:g.68801792A>G, NC_000016.9:g.68835695A>G, CM000678.1:g.68835695A>G, NC_000016.8:g.67393196A>G, NG_008021.1:g.69501A>G, LRG_301:g.69501A>G, NM_004360.4(CDH1):c.286A>G (p.Ile96Val) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Benign BP5 [Unmet], BP7 [Unmet], BS1 [MET], BS4 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet], BS2 [MET], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.286A>G (p.Ile96Val) variant has an allele frequency of 0.00122 (0.12%, 41/33,578 alleles) in the Latino subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA349520/MONDO:0007648/007 0.6752 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 0, 0] 1 Uncertain Significance 11 534287 222076 G A NM_005343.3(HRAS):c.36C>T (p.Gly12=) 222076 CA356960 NM_005343.3:c.36C>T, NC_000011.10:g.534287G>A, CM000673.2:g.534287G>A, NC_000011.9:g.534287G>A, CM000673.1:g.534287G>A, NC_000011.8:g.524287G>A, NG_007666.1:g.6264C>T, NM_001130442.1:c.36C>T, NM_005343.2:c.36C>T, NM_176795.3:c.36C>T, XM_011519875.1:c.-424-4311G>A, XM_011519877.1:c.-161-5293G>A, XR_242795.1:n.235C>T, NM_001130442.2:c.36C>T, NM_001318054.1:c.-284C>T, NM_176795.4:c.36C>T, XM_011519875.2:c.-424-4311G>A, XM_011519877.2:c.-161-5293G>A, XM_017017167.1:c.-499-4236G>A, XM_017017168.1:c.-499-4236G>A, NM_005343.4:c.36C>T, ENST00000311189.7:c.36C>T, ENST00000397594.5:c.36C>T, ENST00000397596.6:c.36C>T, ENST00000417302.5:c.36C>T, ENST00000451590.5:c.36C>T, ENST00000468682.2:n.524C>T, ENST00000482021.1:n.159C>T, ENST00000493230.5:c.36C>T, NM_005343.3(HRAS):c.36C>T (p.Gly12=) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.36C>T (p.Gly12=) variant in the HRAS gene is 0.0461% (8/8626) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA356960/MONDO:0021060/004 0.0122 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 10 89717715 223142 T C NM_000314.6(PTEN):c.740T>C (p.Leu247Ser) 223142 CA16044135 NM_000314.6:c.740T>C, NC_000010.11:g.87957958T>C, CM000672.2:g.87957958T>C, NC_000010.10:g.89717715T>C, CM000672.1:g.89717715T>C, NC_000010.9:g.89707695T>C, NG_007466.2:g.99520T>C, LRG_311:g.99520T>C, NM_000314.5:c.740T>C, NM_001304717.2:c.1259T>C, NM_001304718.1:c.149T>C, XM_006717926.2:c.695T>C, XM_011539981.1:c.740T>C, XM_011539982.1:c.644T>C, XR_945791.1:n.1310T>C, NM_000314.7:c.740T>C, NM_001304717.5:c.1259T>C, NM_001304718.2:c.149T>C, ENST00000371953.7:c.740T>C, ENST00000472832.2:n.167T>C, NM_000314.6(PTEN):c.740T>C (p.Leu247Ser) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [MET], PVS1 [Unmet], BS2 [Unmet], PP1 [Unmet], PP4 [Unmet], PP2 [MET], PP3 [Unmet], PS4-Supporting [MET], BA1 [Unmet], BP2 [Unmet], BP4 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS4 [Unmet], BS1 [Unmet], BS3 [Unmet], BP5 [Unmet], BP7 [Unmet] PTEN c.740T>C (p.Leu247Ser) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 28086757)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28086757) 28086757, 29752200, 28086757, 28086757, 29752200, 28086757, 29752200 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA16044135/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103306627 225133 A G NM_000277.2(PAH):c.110T>C (p.Leu37Pro) 225133 CA357242 NM_000277.2:c.110T>C, NM_000277.1:c.110T>C, XM_011538422.1:c.110T>C, NM_001354304.1:c.110T>C, XM_017019370.2:c.110T>C, NM_000277.3:c.110T>C, ENST00000307000.7:c.95T>C, ENST00000546844.1:c.110T>C, ENST00000548677.2:n.197T>C, ENST00000548928.1:n.32T>C, ENST00000549111.5:n.206T>C, ENST00000550978.6:n.94T>C, ENST00000551337.5:c.110T>C, ENST00000551988.5:n.199T>C, ENST00000553106.5:c.110T>C, ENST00000635500.1:n.78T>C, NC_000012.12:g.102912849A>G, CM000674.2:g.102912849A>G, NC_000012.11:g.103306627A>G, CM000674.1:g.103306627A>G, NC_000012.10:g.101830757A>G, NG_008690.1:g.9754T>C, NG_008690.2:g.50562T>C, NM_000277.2(PAH):c.110T>C (p.Leu37Pro) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM3 [MET], PP3 [MET], PP4 [MET] The c.110T>C (p.Leu37Pro) variant in PAH is reported in 1 patient with mild PKU. Assessment of BH4 deficiencies not reported. It was detected with a known pathogenic variant, p.R408W. (PMID: 24350308) This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, and MutationTaster. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4, PP3. 24350308, 24350308, 24078561 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA357242/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246635 225135 T A NM_000277.2(PAH):c.800A>T (p.Gln267Leu) 225135 CA354145 NM_000277.2:c.800A>T, NM_000277.1:c.800A>T, XM_011538422.1:c.800A>T, NM_001354304.1:c.800A>T, NM_000277.3:c.800A>T, ENST00000307000.7:c.785A>T, ENST00000549247.6:n.559A>T, ENST00000553106.5:c.800A>T, NC_000012.12:g.102852857T>A, CM000674.2:g.102852857T>A, NC_000012.11:g.103246635T>A, CM000674.1:g.103246635T>A, NC_000012.10:g.101770765T>A, NG_008690.1:g.69746A>T, NG_008690.2:g.110554A>T, NM_000277.2(PAH):c.800A>T (p.Gln267Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PP3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD ( 0.00001, 0.000004063); PP3: Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.975; PP4_Moderate: Q267L found in 1 Japanese PKU allele and in 1 Chinese PKU patient. Analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine was performed in the Japanese study. Upgraded per ClinGen Metabolic workgroup. (PMID:21307867; PMID:24078561; PMID:26503515). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate). 26503515, 21307867, 24078561 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA354145/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 14 31354707 226529 G A NM_004086.2(COCH):c.841G>A (p.Asp281Asn) 226529 CA7143202 NM_004086.2:c.841G>A, NC_000014.9:g.30885501G>A, CM000676.2:g.30885501G>A, NC_000014.8:g.31354707G>A, CM000676.1:g.31354707G>A, NC_000014.7:g.30424458G>A, NG_008211.2:g.15967G>A, NM_001135058.1:c.841G>A, NR_038356.1:n.1364C>T, XM_011536539.1:c.841G>A, NM_001347720.1:c.1036G>A, XM_017021071.1:c.1036G>A, XM_024449506.1:c.898G>A, NM_004086.3:c.841G>A, ENST00000216361.8:c.841G>A, ENST00000396618.7:c.841G>A, ENST00000460581.6:c.505G>A, ENST00000468826.2:n.492G>A, ENST00000475087.5:c.841G>A, ENST00000555881.5:c.487G>A, ENST00000557065.1:n.623G>A, NM_004086.2(COCH):c.841G>A (p.Asp281Asn) COCH nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.841G>A (p.Asp281Asn) variant in the COCH gene is 0.5% for African chromosomes by gnomAD (145/24032 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA7143202/MONDO:0019497/005 0.1877 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 1, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 14 31348684 227258 A G NM_004086.2(COCH):c.429A>G (p.Pro143=) 227258 CA7143032 NM_004086.2:c.429A>G, NC_000014.9:g.30879478A>G, CM000676.2:g.30879478A>G, NC_000014.8:g.31348684A>G, CM000676.1:g.31348684A>G, NC_000014.7:g.30418435A>G, NG_008211.2:g.9944A>G, NM_001135058.1:c.429A>G, NR_038356.1:n.1618-2926T>C, XM_011536539.1:c.429A>G, NM_001347720.1:c.624A>G, XM_017021071.1:c.624A>G, XM_024449506.1:c.429A>G, NM_004086.3:c.429A>G, ENST00000216361.8:c.429A>G, ENST00000396618.7:c.429A>G, ENST00000460581.6:c.93A>G, ENST00000475087.5:c.429A>G, ENST00000553772.5:c.240-974A>G, ENST00000553833.5:n.583A>G, ENST00000555881.5:c.83-974A>G, ENST00000556908.5:c.381A>G, ENST00000557065.1:n.211A>G, NM_004086.2(COCH):c.429A>G (p.Pro143=) COCH nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency (the lower threshold of the 95% CI of 44/24026) of the c.429A>G (p.Pro143=) variant in the COCH gene is 0.14% for African chromosomes by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA7143032/MONDO:0019497/005 0.4999 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 1 41285030 227469 C G NM_004700.3(KCNQ4):c.720C>G (p.Thr240=) 227469 CA10576423 NM_004700.3:c.720C>G, NC_000001.11:g.40819358C>G, CM000663.2:g.40819358C>G, NC_000001.10:g.41285030C>G, CM000663.1:g.41285030C>G, NC_000001.9:g.41057617C>G, NG_008139.1:g.40347C>G, NG_008139.2:g.40347C>G, NM_172163.2:c.720C>G, XM_011542417.1:c.720C>G, XM_011542418.1:c.720C>G, XM_011542419.1:c.720C>G, XM_011542420.1:c.720C>G, XR_946798.1:n.726C>G, XR_946799.1:n.726C>G, XR_946800.1:n.726C>G, XM_017002792.1:c.-298C>G, NM_004700.4:c.720C>G, ENST00000347132.9:c.720C>G, ENST00000443478.3:n.406C>G, ENST00000506017.1:n.39C>G, ENST00000509682.6:n.720C>G, NM_004700.3(KCNQ4):c.720C>G (p.Thr240=) KCNQ4 hearing loss MONDO:0005365 Autosomal dominant inheritance Likely Benign PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [MET], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BP7 [MET], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The silent p.Thr240= variant in KCNQ4 is not predicted by computational tools to impact splicing (BP7. BP4). The variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org), however this is not considered evidence against a likely benign classification. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied: BP7, BP4. Hearing Loss EP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-10-02 false https://erepo.genome.network/evrepo/ui/classification/CA10576423/MONDO:0005365/005 0.1877 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 16 68845762 231647 G A NM_004700.3(KCNQ4):c.720C>G (p.Thr240=) 227469 CA10576423 NM_004700.3:c.720C>G, NM_172163.2:c.720C>G, XM_011542417.1:c.720C>G, XM_011542418.1:c.720C>G, XM_011542419.1:c.720C>G, XM_011542420.1:c.720C>G, XR_946798.1:n.726C>G, XR_946799.1:n.726C>G, XR_946800.1:n.726C>G, XM_017002792.1:c.-298C>G, NM_004700.4:c.720C>G, ENST00000347132.9:c.720C>G, ENST00000443478.3:n.406C>G, ENST00000506017.1:n.39C>G, ENST00000509682.6:n.720C>G, NC_000001.11:g.40819358C>G, CM000663.2:g.40819358C>G, NC_000001.10:g.41285030C>G, CM000663.1:g.41285030C>G, NC_000001.9:g.41057617C>G, NG_008139.1:g.40347C>G, NG_008139.2:g.40347C>G, NM_004700.3(KCNQ4):c.720C>G (p.Thr240=) KCNQ4 nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Likely Benign PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [MET], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [MET], BP5 [Unmet] The silent p.Thr240= variant in KCNQ4 is not predicted by computational tools to impact splicing (BP7. BP4). The variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org), however this is not considered evidence against a likely benign classification. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied: BP7, BP4. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA10576423/MONDO:0019497/005 0.4999 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89653805 231916 A G NM_004360.4(CDH1):c.1008G>A (p.Glu336=) 231647 CA10580100 NM_004360.4:c.1008G>A, NM_004360.3:c.1008G>A, LRG_301t1:c.1008G>A, XM_011523488.1:c.273G>A, XM_011523489.1:c.273G>A, NM_001317184.1:c.1008G>A, NM_001317185.1:c.-608G>A, NM_001317186.1:c.-812G>A, ENST00000261769.9:c.1008G>A, ENST00000422392.6:c.1008G>A, ENST00000561751.1:n.630G>A, ENST00000562836.5:n.1079G>A, ENST00000566510.5:c.852G>A, ENST00000566612.5:c.1008G>A, ENST00000611625.4:c.1008G>A, ENST00000612417.4:c.1008G>A, ENST00000621016.4:c.1008G>A, NC_000016.10:g.68811859G>A, CM000678.2:g.68811859G>A, NC_000016.9:g.68845762G>A, CM000678.1:g.68845762G>A, NC_000016.8:g.67403263G>A, NG_008021.1:g.79568G>A, LRG_301:g.79568G>A, NM_004360.4(CDH1):c.1008G>A (p.Glu336=) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Likely Pathogenic BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [MET], PS1 [Unmet], PS4 [Unmet], PS2 [Unmet], PVS1-Moderate [MET] The c.1008G>A p.(Glu336=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 18427545). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Moderate, PM2, PS3. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA10580100/MONDO:0007648/007 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89624244 233415 A G NM_000314.6(PTEN):c.103A>G (p.Met35Val) 231916 CA10578906 NM_000314.6:c.103A>G, NC_000010.11:g.87894048A>G, CM000672.2:g.87894048A>G, NC_000010.10:g.89653805A>G, CM000672.1:g.89653805A>G, NC_000010.9:g.89643785A>G, NG_007466.2:g.35610A>G, LRG_311:g.35610A>G, NM_000314.5:c.103A>G, NM_001304717.2:c.622A>G, NM_001304718.1:c.-603A>G, XM_006717926.2:c.103A>G, XM_011539981.1:c.103A>G, XM_011539982.1:c.68+13610A>G, XR_945789.1:n.815A>G, XR_945790.1:n.815A>G, XR_945791.1:n.815A>G, NM_000314.7:c.103A>G, NM_001304717.5:c.622A>G, NM_001304718.2:c.-603A>G, ENST00000371953.7:c.103A>G, ENST00000462694.1:n.105A>G, ENST00000610634.1:c.1A>G, NM_000314.6(PTEN):c.103A>G (p.Met35Val) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PP2 [MET], PS2 [MET], PS4-Moderate [MET] PTEN c.103A>G (p.M35V) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000275912.5)PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (Internal laboratory contributor(s) SCV000565444.4, SCV000275912.5)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2017-10-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA10578906/MONDO:0017623/003 0.1877 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 16 68853296 234554 C G NM_000314.6(PTEN):c.18A>G (p.Lys6=) 233415 CA10578903 NM_000314.6:c.18A>G, NM_000314.5:c.18A>G, NM_001304717.2:c.537A>G, NM_001304718.1:c.-688A>G, XM_006717926.2:c.18A>G, XM_011539981.1:c.18A>G, XR_945789.1:n.730A>G, XR_945790.1:n.730A>G, XR_945791.1:n.730A>G, NM_000314.7:c.18A>G, NM_001304717.5:c.537A>G, NM_001304718.2:c.-688A>G, ENST00000371953.7:c.18A>G, ENST00000462694.1:n.20A>G, ENST00000487939.1:n.39A>G, ENST00000610634.1:c.-85A>G, NC_000010.11:g.87864487A>G, CM000672.2:g.87864487A>G, NC_000010.10:g.89624244A>G, CM000672.1:g.89624244A>G, NC_000010.9:g.89614224A>G, NG_007466.2:g.6049A>G, LRG_311:g.6049A>G, NG_033079.1:g.3951T>C, NM_000314.6(PTEN):c.18A>G (p.Lys6=) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign BP4 [MET], BP7 [MET] PTEN c.18A>G (p.L6=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2016-10-12 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA10578903/MONDO:0017623/003 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 10 89725110 237639 G A NM_004360.4(CDH1):c.1679C>G (p.Thr560Arg) 234554 CA10577547 NM_004360.4:c.1679C>G, NM_004360.3:c.1679C>G, LRG_301t1:c.1679C>G, XM_011523488.1:c.944C>G, XM_011523489.1:c.944C>G, NM_001317184.1:c.1496C>G, NM_001317185.1:c.131C>G, NM_001317186.1:c.-254-2608C>G, ENST00000261769.9:c.1679C>G, ENST00000422392.6:c.1496C>G, ENST00000562836.5:n.1750C>G, ENST00000566510.5:c.*345C>G, ENST00000566612.5:c.1566-2608C>G, ENST00000611625.4:c.1742C>G, ENST00000612417.4:c.1679C>G, ENST00000621016.4:c.1679C>G, NC_000016.10:g.68819393C>G, CM000678.2:g.68819393C>G, NC_000016.9:g.68853296C>G, CM000678.1:g.68853296C>G, NC_000016.8:g.67410797C>G, NG_008021.1:g.87102C>G, LRG_301:g.87102C>G, NM_004360.4(CDH1):c.1679C>G (p.Thr560Arg) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [MET], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [MET], PS4 [MET], PS1 [Unmet], PS2 [Unmet], PP1-Strong [MET] The c.1679C>G (p.Thr560Arg) variant is absent in the gnomAD cohort (PM2;http://gnomad.broadinstitute.org). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 27880784). Additionally, the variant was found to co-segregation with disease in multiple affected family members, with >7 meioses observed across at least 4 families (PP1_Strong; PMID: 27880784, 29769627). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 27880784, 29769627, 23709761 and SCV000580704.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2, PP3, PS3, PP1_Strong, PS4. 29769627, 29769627, 23709761, 27880784, 29769627 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA10577547/MONDO:0007648/007 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 89685300 237643 C G NM_000314.7(PTEN):c.1093G>A (p.Val365Ile) 237639 CA059160 NM_000314.7:c.1093G>A, NC_000010.11:g.87965353G>A, CM000672.2:g.87965353G>A, NC_000010.10:g.89725110G>A, CM000672.1:g.89725110G>A, NC_000010.9:g.89715090G>A, NG_007466.2:g.106915G>A, LRG_311:g.106915G>A, NM_000314.5:c.1093G>A, NM_000314.6:c.1093G>A, NM_001304717.2:c.1612G>A, NM_001304718.1:c.502G>A, XM_006717926.2:c.1048G>A, XM_011539982.1:c.997G>A, XR_945791.1:n.1663G>A, NM_001304717.5:c.1612G>A, NM_001304718.2:c.502G>A, ENST00000371953.7:c.1093G>A, NM_000314.7(PTEN):c.1093G>A (p.Val365Ile) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [MET], BS4 [Unmet] PTEN c.1093G>A (p.Val365Ile) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 29785012, 29706350) 29706350, 29785012 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA059160/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36164870 239039 C A NM_000314.6(PTEN):c.195C>G (p.Tyr65Ter) 237643 CA10582757 NM_000314.6:c.195C>G, NC_000010.11:g.87925543C>G, CM000672.2:g.87925543C>G, NC_000010.10:g.89685300C>G, CM000672.1:g.89685300C>G, NC_000010.9:g.89675280C>G, NG_007466.2:g.67105C>G, LRG_311:g.67105C>G, NM_000314.5:c.195C>G, NM_001304717.2:c.714C>G, NM_001304718.1:c.-541-5503C>G, XM_006717926.2:c.165-5503C>G, XM_011539981.1:c.195C>G, XM_011539982.1:c.99C>G, XR_945789.1:n.907C>G, XR_945790.1:n.907C>G, XR_945791.1:n.907C>G, NM_000314.7:c.195C>G, NM_001304717.5:c.714C>G, NM_001304718.2:c.-541-5503C>G, ENST00000371953.7:c.195C>G, ENST00000498703.1:n.21C>G, ENST00000610634.1:c.93C>G, NM_000314.6(PTEN):c.195C>G (p.Tyr65Ter) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], BS2 [Unmet], PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], PS4-Supporting [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS2 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet] PTEN c.195C>G (p.Y65X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23335809) 21194675, 23335809, 28454995, 29785012, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10582757/MONDO:0017623/003 0.1 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 21 36164771 239040 C CATGCCG NM_001754.4(RUNX1):c.1005G>T (p.Gln335His) 239039 CA10014223 NM_001754.4:c.1005G>T, NC_000021.9:g.34792573C>A, CM000683.2:g.34792573C>A, NC_000021.8:g.36164870C>A, CM000683.1:g.36164870C>A, NC_000021.7:g.35086740C>A, NG_011402.2:g.1197139G>T, LRG_482:g.1197139G>T, NM_001001890.2:c.924G>T, LRG_482t1:c.1005G>T, XM_005261068.3:c.969G>T, XM_005261069.3:c.813G>T, XM_011529766.1:c.1005G>T, XM_011529767.1:c.966G>T, XM_011529768.1:c.774G>T, XR_937576.1:n.4609G>T, XM_005261069.4:c.813G>T, XM_011529766.2:c.1005G>T, XM_011529767.2:c.966G>T, XM_011529768.2:c.774G>T, XM_017028487.1:c.852G>T, XR_937576.2:n.4656G>T, ENST00000300305.7:c.1005G>T, ENST00000344691.8:c.924G>T, ENST00000399240.5:c.732G>T, ENST00000437180.5:c.1005G>T, ENST00000482318.5:c.*595G>T, NM_001754.4(RUNX1):c.1005G>T (p.Gln335His) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BA1 [MET], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], PP3 [Unmet], PP1 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet] The NM_001754.4:c.1005G>T (p.Gln335His) variant has a MAF of 0.00357 (0.357%, 15/4,206 alleles) in the East Asian subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This missense variant has a REVEL score 0.4. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014223/MONDO:0011071/008 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36164606 239042 G A NM_001754.4(RUNX1):c.1098_1103dupCGGCAT (p.Gly367_Met368insIleGly) 239040 CA10014201 NM_001754.4:c.1098_1103dup6, NM_001754.4:c.1098_1103dupCGGCAT, NC_000021.9:g.34792486_34792491dup, CM000683.2:g.34792486_34792491dup, NC_000021.8:g.36164783_36164788dup, CM000683.1:g.36164783_36164788dup, NC_000021.7:g.35086653_35086658dup, NG_011402.2:g.1197232_1197237dup, LRG_482:g.1197232_1197237dup, NM_001001890.2:c.1017_1022dup, NM_001754.4:c.1098_1103dup, LRG_482t1:c.1098_1103dup, XM_005261068.3:c.1062_1067dup, XM_005261069.3:c.906_911dup, XM_011529766.1:c.1098_1103dup, XM_011529767.1:c.1059_1064dup, XM_011529768.1:c.867_872dup, XM_005261069.4:c.906_911dup, XM_011529766.2:c.1098_1103dup, XM_011529767.2:c.1059_1064dup, XM_011529768.2:c.867_872dup, XM_017028487.1:c.945_950dup, ENST00000300305.7:c.1098_1103dup, ENST00000344691.8:c.1017_1022dup, ENST00000399240.5:c.825_830dup, ENST00000437180.5:c.1098_1103dup, ENST00000482318.5:c.*688_*693dup, NM_001754.4(RUNX1):c.1098_1103dupCGGCAT (p.Gly367_Met368insIleGly) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BA1 [Unmet], BP2 [Unmet], BP4 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4-Moderate [MET], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS4 [Unmet], BS1 [Unmet], BS3 [Unmet], BP7 [Unmet], PP1 [Unmet], PP3 [Unmet], PM6 [Unmet], PM2 [MET], PVS1 [Unmet] The NM_001754.4:c.1098_1103dupCGGCAT (p.Gly367_Met368insIleGly) variant has been reported in two or three probands (two) meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 27210295, PMID: 28659335). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_moderate, PM2. 27210295, 28659335 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014201/MONDO:0011071/008 0.0014 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 21 36259336 239044 A T NM_001754.4(RUNX1):c.1269C>T (p.Arg423=) 239042 CA10014189 NM_001754.4:c.1269C>T, NC_000021.9:g.34792309G>A, CM000683.2:g.34792309G>A, NC_000021.8:g.36164606G>A, CM000683.1:g.36164606G>A, NC_000021.7:g.35086476G>A, NG_011402.2:g.1197403C>T, LRG_482:g.1197403C>T, NM_001001890.2:c.1188C>T, LRG_482t1:c.1269C>T, XM_005261068.3:c.1233C>T, XM_005261069.3:c.1077C>T, XM_011529766.1:c.1269C>T, XM_011529767.1:c.1230C>T, XM_011529768.1:c.1038C>T, XM_005261069.4:c.1077C>T, XM_011529766.2:c.1269C>T, XM_011529767.2:c.1230C>T, XM_011529768.2:c.1038C>T, XM_017028487.1:c.1116C>T, ENST00000300305.7:c.1269C>T, ENST00000344691.8:c.1188C>T, ENST00000399240.5:c.996C>T, ENST00000437180.5:c.1269C>T, ENST00000482318.5:c.*859C>T, NM_001754.4(RUNX1):c.1269C>T (p.Arg423=) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BP4 [MET], BP2 [Unmet], BA1 [MET], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM4 [Unmet], PM5 [Unmet], PM1 [Unmet], BP7 [Unmet], BS3 [Unmet], BS4 [Unmet], BS1 [Unmet], PP3 [Unmet], PP1 [Unmet], PM6 [Unmet], PM2 [Unmet], PVS1 [Unmet] The MAF for the synonymous variant, NM_001754.4:c.1269C>T (p.Arg423=) is 0.00275 (0.2%, 14/5096 alleles) in the non-Finnish European subpopulation of the ExAC cohort, which is ≥ 0.0015 (0.15%) (BA1). This variant is predicted by SSF and MES to lead to an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% AND no putative cryptic splice sites are created (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014189/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 21 36259324 239045 A G NM_001754.4(RUNX1):c.155T>A (p.Met52Lys) 239044 CA10014581 NM_001754.4:c.155T>A, NM_001001890.2:c.74T>A, NM_001122607.1:c.74T>A, LRG_482t1:c.155T>A, XM_005261068.3:c.119T>A, XM_005261069.3:c.155T>A, XM_011529766.1:c.155T>A, XM_011529767.1:c.116T>A, XM_011529768.1:c.116T>A, XM_011529770.1:c.155T>A, XR_937576.1:n.334T>A, XM_005261069.4:c.155T>A, XM_011529766.2:c.155T>A, XM_011529767.2:c.116T>A, XM_011529768.2:c.116T>A, XM_011529770.2:c.155T>A, XM_017028487.1:c.2T>A, XR_937576.2:n.381T>A, ENST00000300305.7:c.155T>A, ENST00000344691.8:c.74T>A, ENST00000358356.9:c.74T>A, ENST00000399237.6:c.119T>A, ENST00000399240.5:c.74T>A, ENST00000437180.5:c.155T>A, ENST00000455571.5:c.116T>A, ENST00000482318.5:c.59-6326T>A, NC_000021.9:g.34887039A>T, CM000683.2:g.34887039A>T, NC_000021.8:g.36259336A>T, CM000683.1:g.36259336A>T, NC_000021.7:g.35181206A>T, NG_011402.2:g.1102673T>A, LRG_482:g.1102673T>A, NM_001754.4(RUNX1):c.155T>A (p.Met52Lys) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [MET], BS4 [Unmet], PP3 [MET], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.155T>A (p.Met52Lys) variant has a MAF of 0.00071 (0.071%, 6/8,456 alleles) in the EA Allele subpopulation of the ESP cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.845) (PP3). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, PP3. 29365323 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014581/MONDO:0011071/008 0.0014 Benign Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 21 36206858 239052 G A NM_001754.4(RUNX1):c.167T>C (p.Leu56Ser) 239045 CA10014578 NM_001754.4:c.167T>C, NM_001001890.2:c.86T>C, NM_001122607.1:c.86T>C, LRG_482t1:c.167T>C, XM_005261068.3:c.131T>C, XM_005261069.3:c.167T>C, XM_011529766.1:c.167T>C, XM_011529767.1:c.128T>C, XM_011529768.1:c.128T>C, XM_011529770.1:c.167T>C, XR_937576.1:n.346T>C, XM_005261069.4:c.167T>C, XM_011529766.2:c.167T>C, XM_011529767.2:c.128T>C, XM_011529768.2:c.128T>C, XM_011529770.2:c.167T>C, XM_017028487.1:c.14T>C, XR_937576.2:n.393T>C, ENST00000300305.7:c.167T>C, ENST00000344691.8:c.86T>C, ENST00000358356.9:c.86T>C, ENST00000399237.6:c.131T>C, ENST00000399240.5:c.86T>C, ENST00000437180.5:c.167T>C, ENST00000455571.5:c.128T>C, ENST00000482318.5:c.59-6314T>C, NC_000021.9:g.34887027A>G, CM000683.2:g.34887027A>G, NC_000021.8:g.36259324A>G, CM000683.1:g.36259324A>G, NC_000021.7:g.35181194A>G, NG_011402.2:g.1102685T>C, LRG_482:g.1102685T>C, NM_001754.4(RUNX1):c.167T>C (p.Leu56Ser) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BP4 [Unmet], BP2 [MET], BA1 [MET], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BS3 [MET], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.167T>C (p.Leu56Ser) variant has a MAF of 0.03259 (3.259%, 518/15,894 alleles) in the South Asian subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (56) in gnomAD population database (BP2). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization (BS3; PMID: 23817177). Two patients reported in PMID:29365323 with AML. But PS4 can not apply in combined with BA1. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BS3, BP2. 23817177 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014578/MONDO:0011071/008 0.0014 Benign Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 16 68771321 239906 G A NM_001754.4(RUNX1):c.654C>T (p.Ser218=) 239052 CA10014384 NM_001754.4:c.654C>T, NC_000021.9:g.34834561G>A, CM000683.2:g.34834561G>A, NC_000021.8:g.36206858G>A, CM000683.1:g.36206858G>A, NC_000021.7:g.35128728G>A, NG_011402.2:g.1155151C>T, LRG_482:g.1155151C>T, NM_001001890.2:c.573C>T, NM_001122607.1:c.573C>T, LRG_482t1:c.654C>T, XM_005261068.3:c.618C>T, XM_005261069.3:c.613+24913C>T, XM_011529766.1:c.654C>T, XM_011529767.1:c.615C>T, XM_011529768.1:c.574+24913C>T, XM_011529770.1:c.654C>T, XR_937576.1:n.833C>T, XM_005261069.4:c.613+24913C>T, XM_011529766.2:c.654C>T, XM_011529767.2:c.615C>T, XM_011529768.2:c.574+24913C>T, XM_011529770.2:c.654C>T, XM_017028487.1:c.501C>T, XR_937576.2:n.880C>T, ENST00000300305.7:c.654C>T, ENST00000344691.8:c.573C>T, ENST00000358356.9:c.573C>T, ENST00000399237.6:c.618C>T, ENST00000399240.5:c.532+24913C>T, ENST00000437180.5:c.654C>T, ENST00000469087.1:n.190C>T, ENST00000482318.5:c.*244C>T, NM_001754.4(RUNX1):c.654C>T (p.Ser218=) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Benign BP2 [Unmet], BP4 [MET], BA1 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS4 [Unmet], PS1 [Unmet], PS3 [Unmet], BP7 [Unmet], BS1 [MET], BS4 [Unmet], BS3 [Unmet], PP1 [Unmet], PP3 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The MAF of the synonymous variant, NM_001754.4:c.654C>T (p.Ser218=), is 0.00105 (0.1%, 36/34418 alleles) in the Latino subpopulation of the gnomAD cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This synonymous variant is predicted by SSF and MES to lead to an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% AND no putative cryptic splice sites are created (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014384/MONDO:0011071/008 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68844245 239914 G T NM_004360.4(CDH1):c.3G>A (p.Met1Ile) 239906 CA10583399 NM_004360.4:c.3G>A, NC_000016.10:g.68737418G>A, CM000678.2:g.68737418G>A, NC_000016.9:g.68771321G>A, CM000678.1:g.68771321G>A, NC_000016.8:g.67328822G>A, NG_008021.1:g.5127G>A, LRG_301:g.5127G>A, NM_004360.3:c.3G>A, LRG_301t1:c.3G>A, NM_001317184.1:c.3G>A, NM_001317185.1:c.-1613G>A, NM_001317186.1:c.-1817G>A, ENST00000261769.9:c.3G>A, ENST00000422392.6:c.3G>A, ENST00000566510.5:c.3G>A, ENST00000566612.5:c.3G>A, ENST00000611625.4:c.3G>A, ENST00000612417.4:c.3G>A, ENST00000621016.4:c.3G>A, NM_004360.4(CDH1):c.3G>A (p.Met1Ile) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Likely Pathogenic BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PP1-Moderate [MET], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS4-Moderate [MET], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PVS1-Moderate [MET] The c.3G>A (p.Met1Ile) variant may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (18726070, 2317870, 20066110) (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; PMID: 28202063, 26182300). This variant has also been reported in at least 2 families meeting HDGC clinical criteria (PS4_Moderate; PMID: 26182300, 20719348). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Moderate, PM2, PP1_Moderate, PS4_Moderate. 26182300, 28202063, 26182300, 28202063, 26182300, 20719348, 16061854 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA10583399/MONDO:0007648/007 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89717626 255814 C T NM_004360.4(CDH1):c.832+1G>T 239914 CA10583412 NM_004360.4:c.832+1G>T, NM_004360.3:c.832+1G>T, LRG_301t1:c.832+1G>T, XM_011523488.1:c.97+1G>T, XM_011523489.1:c.97+1G>T, NM_001317184.1:c.832+1G>T, NM_001317185.1:c.-784+1G>T, NM_001317186.1:c.-988+1G>T, ENST00000261769.9:c.832+1G>T, ENST00000422392.6:c.832+1G>T, ENST00000561751.1:n.455-1342G>T, ENST00000562836.5:n.903+1G>T, ENST00000566510.5:c.676+1G>T, ENST00000566612.5:c.832+1G>T, ENST00000611625.4:c.832+1G>T, ENST00000612417.4:c.832+1G>T, ENST00000621016.4:c.832+1G>T, NC_000016.10:g.68810342G>T, CM000678.2:g.68810342G>T, NC_000016.9:g.68844245G>T, CM000678.1:g.68844245G>T, NC_000016.8:g.67401746G>T, NG_008021.1:g.78051G>T, LRG_301:g.78051G>T, NM_004360.4(CDH1):c.832+1G>T CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PM2 [MET], PM6 [Unmet], PP3 [Unmet], PP1 [Unmet], BS2 [Unmet], PM4 [Unmet], PVS1-Strong [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS4 [MET], PS3 [Unmet], PS2 [Unmet] The c.832+G>T variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). The variant is present in <1/100,000 alleles in the gnomAD cohort. (PM2; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 23709761, 23124477, 26182300 and SCV000288497.3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Strong, PM2, PS4. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA10583412/MONDO:0007648/007 0.3246 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 21 36164486 258184 G C NM_000314.6(PTEN):c.651C>T (p.Val217=) 255814 CA10587096 NM_000314.6:c.651C>T, NC_000010.11:g.87957869C>T, CM000672.2:g.87957869C>T, NC_000010.10:g.89717626C>T, CM000672.1:g.89717626C>T, NC_000010.9:g.89707606C>T, NG_007466.2:g.99431C>T, LRG_311:g.99431C>T, NM_000314.5:c.651C>T, NM_001304717.2:c.1170C>T, NM_001304718.1:c.60C>T, XM_006717926.2:c.606C>T, XM_011539981.1:c.651C>T, XM_011539982.1:c.555C>T, XR_945791.1:n.1221C>T, NM_000314.7:c.651C>T, NM_001304717.5:c.1170C>T, NM_001304718.2:c.60C>T, ENST00000371953.7:c.651C>T, ENST00000472832.2:n.78C>T, NM_000314.6(PTEN):c.651C>T (p.Val217=) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Benign PM2 [MET], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [MET], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [MET], BP5 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.651C>T (p.V217=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-07-25 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA10587096/MONDO:0017623/003 0.0003 Benign Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=1 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 21 36259125 258185 T C NM_001754.4(RUNX1):c.1389C>G (p.Pro463=) 258184 CA10014178 NM_001754.4:c.1389C>G, NM_001001890.2:c.1308C>G, LRG_482t1:c.1389C>G, XM_005261068.3:c.1353C>G, XM_005261069.3:c.1197C>G, XM_011529766.1:c.1389C>G, XM_011529767.1:c.1350C>G, XM_011529768.1:c.1158C>G, XM_005261069.4:c.1197C>G, XM_011529766.2:c.1389C>G, XM_011529767.2:c.1350C>G, XM_011529768.2:c.1158C>G, XM_017028487.1:c.1236C>G, ENST00000300305.7:c.1389C>G, ENST00000344691.8:c.1308C>G, ENST00000399240.5:c.1116C>G, ENST00000437180.5:c.1389C>G, ENST00000482318.5:c.*979C>G, NC_000021.9:g.34792189G>C, CM000683.2:g.34792189G>C, NC_000021.8:g.36164486G>C, CM000683.1:g.36164486G>C, NC_000021.7:g.35086356G>C, NG_011402.2:g.1197523C>G, LRG_482:g.1197523C>G, NM_001754.4(RUNX1):c.1389C>G (p.Pro463=) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BA1 [MET], BP4 [MET], BP2 [MET], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], BP7 [MET], BS3 [Unmet], BS4 [Unmet], BS1 [Unmet], PP3 [Unmet], PP1 [Unmet], PM6 [Unmet], PM2 [Unmet], PVS1 [Unmet] The MAF for the synonymous variant, NM_001754.4:c.1389C>G (p.Pro463=) is 0.1206 (12%, 1976/16382 alleles) in the African subpopulation of the gnomAD cohort, which is ≥ 0.0015 (0.15%) (BA1). This variant is predicted by SSF and MES to lead to an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% AND no putative cryptic splice sites are created (BP4). This synonymous variant is predicted by evolutionary conservation prediction algorithms that the site is not conserved (PhyloP score -0.503315 <0.1) (BP7). This variant is detected in a homozygous state in 202 individuals in a gnomAD (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. 27106701 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false 0.0007 Benign Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 21 36206932 258186 G A NM_001754.4(RUNX1):c.351+15A>G 258185 CA10014545 NM_001754.4:c.351+15A>G, NM_001001890.2:c.270+15A>G, NM_001122607.1:c.270+15A>G, LRG_482t1:c.351+15A>G, XM_005261068.3:c.315+15A>G, XM_005261069.3:c.351+15A>G, XM_011529766.1:c.351+15A>G, XM_011529767.1:c.312+15A>G, XM_011529768.1:c.312+15A>G, XM_011529770.1:c.351+15A>G, XR_937576.1:n.530+15A>G, XM_005261069.4:c.351+15A>G, XM_011529766.2:c.351+15A>G, XM_011529767.2:c.312+15A>G, XM_011529768.2:c.312+15A>G, XM_011529770.2:c.351+15A>G, XM_017028487.1:c.198+15A>G, XR_937576.2:n.577+15A>G, ENST00000300305.7:c.351+15A>G, ENST00000344691.8:c.270+15A>G, ENST00000358356.9:c.270+15A>G, ENST00000399237.6:c.315+15A>G, ENST00000399240.5:c.270+15A>G, ENST00000437180.5:c.351+15A>G, ENST00000455571.5:c.312+15A>G, ENST00000482318.5:c.59-6115A>G, NC_000021.9:g.34886828T>C, CM000683.2:g.34886828T>C, NC_000021.8:g.36259125T>C, CM000683.1:g.36259125T>C, NC_000021.7:g.35180995T>C, NG_011402.2:g.1102884A>G, LRG_482:g.1102884A>G, NM_001754.4(RUNX1):c.351+15A>G RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BA1 [MET], BP4 [MET], BP2 [MET], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [MET], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.351+15A>G variant has a MAF of 0.00809 (0.809%, 524/64,760 alleles) in the European (Non-Finnish) subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (8) in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -1.34728 < 0.1) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014545/MONDO:0011071/008 0 Benign auto Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=1 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 11 533534 259747 G A NM_001754.4(RUNX1):c.614-34C>T 258186 CA10014405 NM_001754.4:c.614-34C>T, NM_001001890.2:c.533-34C>T, NM_001122607.1:c.533-34C>T, LRG_482t1:c.614-34C>T, XM_005261068.3:c.578-34C>T, XM_005261069.3:c.613+24839C>T, XM_011529766.1:c.614-34C>T, XM_011529767.1:c.575-34C>T, XM_011529768.1:c.574+24839C>T, XM_011529770.1:c.614-34C>T, XR_937576.1:n.793-34C>T, XM_005261069.4:c.613+24839C>T, XM_011529766.2:c.614-34C>T, XM_011529767.2:c.575-34C>T, XM_011529768.2:c.574+24839C>T, XM_011529770.2:c.614-34C>T, XM_017028487.1:c.461-34C>T, XR_937576.2:n.840-34C>T, ENST00000300305.7:c.614-34C>T, ENST00000344691.8:c.533-34C>T, ENST00000358356.9:c.533-34C>T, ENST00000399237.6:c.578-34C>T, ENST00000399240.5:c.532+24839C>T, ENST00000437180.5:c.614-34C>T, ENST00000469087.1:n.150-34C>T, ENST00000482318.5:c.*204-34C>T, NC_000021.9:g.34834635G>A, CM000683.2:g.34834635G>A, NC_000021.8:g.36206932G>A, CM000683.1:g.36206932G>A, NC_000021.7:g.35128802G>A, NG_011402.2:g.1155077C>T, LRG_482:g.1155077C>T, NM_001754.4(RUNX1):c.614-34C>T RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BA1 [MET], BP4 [MET], BP2 [MET], PS3 [Unmet], PS1 [Unmet], PS4 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.614-34C>T variant has a MAF of 1 (100%) in gnomAD cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014405/MONDO:0011071/008 0.025 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 19 4094469 261928 C T NM_005343.3(HRAS):c.369C>T (p.Arg123=) 259747 CA5779327 NM_005343.3:c.369C>T, NM_001130442.1:c.369C>T, NM_005343.2:c.369C>T, NM_176795.3:c.369C>T, XM_011519875.1:c.-424-5064G>A, XM_011519877.1:c.-162+5197G>A, XR_242795.1:n.568C>T, NM_001130442.2:c.369C>T, NM_001318054.1:c.50C>T, NM_176795.4:c.369C>T, XM_011519875.2:c.-424-5064G>A, XM_011519877.2:c.-162+5197G>A, XM_017017167.1:c.-499-4989G>A, XM_017017168.1:c.-499-4989G>A, NM_005343.4:c.369C>T, ENST00000311189.7:c.369C>T, ENST00000397594.5:c.369C>T, ENST00000397596.6:c.369C>T, ENST00000417302.5:c.369C>T, ENST00000451590.5:c.369C>T, ENST00000462734.1:n.62C>T, ENST00000478324.5:n.79C>T, ENST00000479482.1:n.290C>T, ENST00000493230.5:c.369C>T, NC_000011.10:g.533534G>A, CM000673.2:g.533534G>A, NC_000011.9:g.533534G>A, CM000673.1:g.533534G>A, NC_000011.8:g.523534G>A, NG_007666.1:g.7017C>T, NM_005343.3(HRAS):c.369C>T (p.Arg123=) LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.369C>T (p.Arg123=) variant in the HRAS gene is 0.089% (13/8638) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA5779327/MONDO:0021060/004 0.0003 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 12 103238196 281073 G A NM_030662.3(MAP2K2):c.1074G>A (p.Ala358=) 261928 CA9090706 NM_030662.3:c.1074G>A, NC_000019.10:g.4094471C>T, CM000681.2:g.4094471C>T, NC_000019.9:g.4094469C>T, CM000681.1:g.4094469C>T, NC_000019.8:g.4045469C>T, NG_007996.1:g.34658G>A, LRG_750:g.34658G>A, LRG_750t1:c.1074G>A, XM_006722799.2:c.795G>A, XM_011528133.1:c.504G>A, ENST00000262948.9:c.1074G>A, ENST00000394867.8:c.783G>A, ENST00000597263.5:n.259G>A, ENST00000599021.1:n.184G>A, ENST00000600584.5:n.2523G>A, ENST00000601786.5:n.1375G>A, NM_030662.3(MAP2K2):c.1074G>A (p.Ala358=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1074G>A (p.Ala358=) variant in the MAP2K2 gene is 0.174% (10/3124) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA9090706/MONDO:0021060/004 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 14 31349945 281981 C T NM_000277.1(PAH):c.983C>T (p.Thr328Ile) 281073 CA10603804 NM_000277.1:c.983C>T, XM_011538422.1:c.926C>T, NM_000277.2:c.983C>T, NM_001354304.1:c.983C>T, NM_000277.3:c.983C>T, ENST00000307000.7:c.968C>T, ENST00000549247.6:n.742C>T, ENST00000551114.2:n.645C>T, ENST00000553106.5:c.983C>T, ENST00000635477.1:n.87C>T, ENST00000635528.1:n.498C>T, NC_000012.12:g.102844418G>A, CM000674.2:g.102844418G>A, NC_000012.11:g.103238196G>A, CM000674.1:g.103238196G>A, NC_000012.10:g.101762326G>A, NG_008690.1:g.78185C>T, NG_008690.2:g.118993C>T, NM_000277.1(PAH):c.983C>T (p.Thr328Ile) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM5 [Unmet], PP3 [MET] PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Predicted deleterious in SIFT, PolyPhen2, Mutation Taster. REVEL=0.952. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA10603804/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 1 215802181 282144 G C NM_004086.2(COCH):c.629+5C>T 281981 CA7143097 NM_004086.2:c.629+5C>T, NM_001135058.1:c.629+5C>T, NR_038356.1:n.1617+3771G>A, XM_011536539.1:c.629+5C>T, NM_001347720.1:c.824+5C>T, XM_017021071.1:c.824+5C>T, XM_024449506.1:c.629+5C>T, NM_004086.3:c.629+5C>T, ENST00000216361.8:c.629+5C>T, ENST00000396618.7:c.629+5C>T, ENST00000460581.6:c.293+5C>T, ENST00000468826.2:n.148+5C>T, ENST00000475087.5:c.629+5C>T, ENST00000553772.5:c.*189+5C>T, ENST00000555881.5:c.275+5C>T, ENST00000557065.1:n.411+5C>T, NC_000014.9:g.30880739C>T, CM000676.2:g.30880739C>T, NC_000014.8:g.31349945C>T, CM000676.1:g.31349945C>T, NC_000014.7:g.30419696C>T, NG_008211.2:g.11205C>T, NM_004086.2(COCH):c.629+5C>T COCH nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.629+5C>T variant in the COCH gene is 0.1% for European chromosomes by gnomAD (162/126474 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA7143097/MONDO:0019497/005 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288566 306914 T C NM_206933.2(USH2A):c.15494C>G (p.Ala5165Gly) 282144 CA1392668 NM_206933.2:c.15494C>G, NM_206933.3:c.15494C>G, ENST00000307340.7:c.15494C>G, NC_000001.11:g.215628839G>C, CM000663.2:g.215628839G>C, NC_000001.10:g.215802181G>C, CM000663.1:g.215802181G>C, NC_000001.9:g.213868804G>C, NG_009497.1:g.799558C>G, NM_206933.2(USH2A):c.15494C>G (p.Ala5165Gly) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Likely Benign PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], BS1-Supporting [MET], BA1 [Unmet], BP4 [MET], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS4 [Unmet] The filtering allele frequency of the p.Ala5165Gly variant in the USH2A gene is 0.21% (63/24034) of African chromosomes chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied (BS1_Supporting, BP4). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1392668/MONDO:0019501/005 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 112915678 307226 G A NM_000277.2(PAH):c.299A>G (p.His100Arg) 306914 CA6748985 NM_000277.2:c.299A>G, NM_000277.1:c.299A>G, XM_011538422.1:c.299A>G, NM_001354304.1:c.299A>G, XM_017019370.2:c.299A>G, NM_000277.3:c.299A>G, ENST00000307000.7:c.284A>G, ENST00000546844.1:c.299A>G, ENST00000548928.1:n.221A>G, ENST00000549111.5:n.395A>G, ENST00000550978.6:n.283A>G, ENST00000551337.5:c.299A>G, ENST00000551988.5:n.388A>G, ENST00000553106.5:c.299A>G, NC_000012.12:g.102894788T>C, CM000674.2:g.102894788T>C, NC_000012.11:g.103288566T>C, CM000674.1:g.103288566T>C, NC_000012.10:g.101812696T>C, NG_008690.1:g.27815A>G, NG_008690.2:g.68623A>G, NM_000277.2(PAH):c.299A>G (p.His100Arg) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [Unmet], PM3 [MET], PP4 [MET], BP4 [MET] PAH-specific ACMG/AMP criteria applied: BP4: In silico overwhelmingly predict benign. REVEL = 0.553; PP4: Detected in a patient with non PKU hyperphe (PMID:11244681); PM3: H100R detected with IVS10 (PMID:11244681). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BP4, PP4, PM3). 11244681, 11244681 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6748985/MONDO:0009861/006 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 21 36164453 339874 C A NM_002834.4(PTPN11):c.951G>A (p.Lys317=) 307226 CA6798691 NM_002834.4:c.951G>A, NM_002834.3:c.951G>A, LRG_614t1:c.951G>A, NM_080601.1:c.951G>A, XM_006719526.1:c.951G>A, XM_006719527.1:c.837G>A, XM_011538613.1:c.948G>A, NM_001330437.1:c.951G>A, NM_080601.2:c.951G>A, XM_011538613.2:c.948G>A, XM_017019722.1:c.948G>A, ENST00000351677.6:c.951G>A, ENST00000392597.5:c.951G>A, ENST00000635625.1:n.951G>A, NC_000012.12:g.112477874G>A, CM000674.2:g.112477874G>A, NC_000012.11:g.112915678G>A, CM000674.1:g.112915678G>A, NC_000012.10:g.111400061G>A, NG_007459.1:g.64143G>A, LRG_614:g.64143G>A, NM_002834.4(PTPN11):c.951G>A (p.Lys317=) PTPN11 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.951G>A (p.Lys317=) variant in the PTPN11 gene is 0.231% (49/16480) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6798691/MONDO:0021060/004 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 0, 0] 2 Uncertain Significance 21 36164520 339875 A C NM_001754.4(RUNX1):c.1422G>T (p.Glu474Asp) 339874 CA10652929 NM_001754.4:c.1422G>T, NM_001001890.2:c.1341G>T, LRG_482t1:c.1422G>T, XM_005261068.3:c.1386G>T, XM_005261069.3:c.1230G>T, XM_011529766.1:c.1422G>T, XM_011529767.1:c.1383G>T, XM_011529768.1:c.1191G>T, XM_005261069.4:c.1230G>T, XM_011529766.2:c.1422G>T, XM_011529767.2:c.1383G>T, XM_011529768.2:c.1191G>T, XM_017028487.1:c.1269G>T, ENST00000300305.7:c.1422G>T, ENST00000344691.8:c.1341G>T, ENST00000399240.5:c.1149G>T, ENST00000437180.5:c.1422G>T, ENST00000482318.5:c.*1012G>T, NC_000021.9:g.34792156C>A, CM000683.2:g.34792156C>A, NC_000021.8:g.36164453C>A, CM000683.1:g.36164453C>A, NC_000021.7:g.35086323C>A, NG_011402.2:g.1197556G>T, LRG_482:g.1197556G>T, NM_001754.4(RUNX1):c.1422G>T (p.Glu474Asp) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BA1 [Unmet], BP2 [Unmet], BP4 [Unmet], PS4 [Unmet], PS1 [Unmet], PS3 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet], BS3 [Unmet], PP1 [Unmet], PP3 [Unmet], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.1422G>T (p.Glu474Asp) variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score 0.312. In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10652929/MONDO:0011071/008 0.3246 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 0, 0] 1 Uncertain Significance 21 36231763 339876 G A NM_001754.4(RUNX1):c.1355T>G (p.Val452Gly) 339875 CA10014181 NM_001754.4:c.1355T>G, NM_001001890.2:c.1274T>G, LRG_482t1:c.1355T>G, XM_005261068.3:c.1319T>G, XM_005261069.3:c.1163T>G, XM_011529766.1:c.1355T>G, XM_011529767.1:c.1316T>G, XM_011529768.1:c.1124T>G, XM_005261069.4:c.1163T>G, XM_011529766.2:c.1355T>G, XM_011529767.2:c.1316T>G, XM_011529768.2:c.1124T>G, XM_017028487.1:c.1202T>G, ENST00000300305.7:c.1355T>G, ENST00000344691.8:c.1274T>G, ENST00000399240.5:c.1082T>G, ENST00000437180.5:c.1355T>G, ENST00000482318.5:c.*945T>G, NC_000021.9:g.34792223A>C, CM000683.2:g.34792223A>C, NC_000021.8:g.36164520A>C, CM000683.1:g.36164520A>C, NC_000021.7:g.35086390A>C, NG_011402.2:g.1197489T>G, LRG_482:g.1197489T>G, NM_001754.4(RUNX1):c.1355T>G (p.Val452Gly) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BP4 [MET], BP2 [Unmet], BA1 [MET], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], BP7 [Unmet], BS3 [MET], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.1355T>G (p.Val452Gly) variant has a MAF of 0.00177 (0.177%, 22/12,406 alleles) in the East Asian subpopulation of the gnomAD cohort that is ≥ 0.0015 (0.15%) (BA1). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding and CBFβ binding (BS3; PMID: 25840971). This missense variant has a REVEL score <0.15 (0.046) and SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BS3, BP4. 25840971 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014181/MONDO:0011071/008 0.0003 Benign Benign InterVar: Benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 2 Uncertain Significance 21 36252918 339877 G A NM_001754.4(RUNX1):c.613+8C>T 339876 CA10014475 NM_001754.4:c.613+8C>T, NC_000021.9:g.34859466G>A, CM000683.2:g.34859466G>A, NC_000021.8:g.36231763G>A, CM000683.1:g.36231763G>A, NC_000021.7:g.35153633G>A, NG_011402.2:g.1130246C>T, LRG_482:g.1130246C>T, NM_001001890.2:c.532+8C>T, NM_001122607.1:c.532+8C>T, LRG_482t1:c.613+8C>T, XM_005261068.3:c.577+8C>T, XM_005261069.3:c.613+8C>T, XM_011529766.1:c.613+8C>T, XM_011529767.1:c.574+8C>T, XM_011529768.1:c.574+8C>T, XM_011529770.1:c.613+8C>T, XR_937576.1:n.792+8C>T, XM_005261069.4:c.613+8C>T, XM_011529766.2:c.613+8C>T, XM_011529767.2:c.574+8C>T, XM_011529768.2:c.574+8C>T, XM_011529770.2:c.613+8C>T, XM_017028487.1:c.460+8C>T, XR_937576.2:n.839+8C>T, ENST00000300305.7:c.613+8C>T, ENST00000344691.8:c.532+8C>T, ENST00000358356.9:c.532+8C>T, ENST00000399237.6:c.577+8C>T, ENST00000399240.5:c.532+8C>T, ENST00000437180.5:c.613+8C>T, ENST00000467577.1:n.105+8C>T, ENST00000482318.5:c.*203+8C>T, NM_001754.4(RUNX1):c.613+8C>T RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BP2 [MET], BP4 [MET], BA1 [MET], PS4 [Unmet], PS1 [Unmet], PS3 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [MET], BS4 [Unmet], BS1 [Unmet], BS3 [Unmet], PP1 [Unmet], PP3 [Unmet], PM6 [Unmet], PM2 [Unmet], PVS1 [Unmet] The NM_001754.4:c.613+8C>T variant has a MAF of 0.00151 (0.151%, 101/66,722 alleles) in the European (Non-Finnish) subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (15) in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -1.2534 < 0.1) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014475/MONDO:0011071/008 0.4999 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 21 36265218 339878 A C NM_001754.4(RUNX1):c.444C>T (p.Thr148=) 339877 CA10014514 NM_001754.4:c.444C>T, NM_001001890.2:c.363C>T, NM_001122607.1:c.363C>T, LRG_482t1:c.444C>T, XM_005261068.3:c.408C>T, XM_005261069.3:c.444C>T, XM_011529766.1:c.444C>T, XM_011529767.1:c.405C>T, XM_011529768.1:c.405C>T, XM_011529770.1:c.444C>T, XR_937576.1:n.623C>T, XM_005261069.4:c.444C>T, XM_011529766.2:c.444C>T, XM_011529767.2:c.405C>T, XM_011529768.2:c.405C>T, XM_011529770.2:c.444C>T, XM_017028487.1:c.291C>T, XR_937576.2:n.670C>T, ENST00000300305.7:c.444C>T, ENST00000344691.8:c.363C>T, ENST00000358356.9:c.363C>T, ENST00000399237.6:c.408C>T, ENST00000399240.5:c.363C>T, ENST00000437180.5:c.444C>T, ENST00000455571.5:c.405C>T, ENST00000482318.5:c.*34C>T, NC_000021.9:g.34880621G>A, CM000683.2:g.34880621G>A, NC_000021.8:g.36252918G>A, CM000683.1:g.36252918G>A, NC_000021.7:g.35174788G>A, NG_011402.2:g.1109091C>T, LRG_482:g.1109091C>T, NM_001754.4(RUNX1):c.444C>T (p.Thr148=) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Benign BA1 [Unmet], BP4 [MET], BP2 [Unmet], PS3 [Unmet], PS1 [Unmet], PS4 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BP7 [MET], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.444C>T (p.Thr148=) variant is a synonymous variant that is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -4.3832 < 0.1) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014514/MONDO:0011071/008 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 3 12660096 343103 G A NM_001754.4(RUNX1):c.97+4T>G 339878 CA10014626 NM_001754.4:c.97+4T>G, NC_000021.9:g.34892921A>C, CM000683.2:g.34892921A>C, NC_000021.8:g.36265218A>C, CM000683.1:g.36265218A>C, NC_000021.7:g.35187088A>C, NG_011402.2:g.1096791T>G, LRG_482:g.1096791T>G, LRG_482t1:c.97+4T>G, XM_005261069.3:c.97+4T>G, XM_011529766.1:c.97+4T>G, XM_011529767.1:c.59-5825T>G, XM_011529768.1:c.59-5825T>G, XM_011529770.1:c.97+4T>G, XR_937576.1:n.276+4T>G, XM_005261069.4:c.97+4T>G, XM_011529766.2:c.97+4T>G, XM_011529767.2:c.59-5825T>G, XM_011529768.2:c.59-5825T>G, XM_011529770.2:c.97+4T>G, XR_937576.2:n.323+4T>G, ENST00000300305.7:c.97+4T>G, ENST00000437180.5:c.97+4T>G, ENST00000455571.5:c.59-5825T>G, ENST00000475045.6:c.97+4T>G, ENST00000482318.5:c.59-12208T>G, NM_001754.4(RUNX1):c.97+4T>G RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BA1 [Unmet], BP4 [MET], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS3 [Unmet], BS4 [Unmet], BS1 [Unmet], BP7 [Unmet], PP3 [Unmet], PP1 [Unmet], PVS1 [Unmet], PM6 [Unmet], PM2 [Unmet] The NM_001754.4:c.97+4T>G variant is an intronic variant predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). The gnomAD Allele Frequency of this variant is 0.00003. In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014626/MONDO:0011071/008 0.0028 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103237476 370701 G A NM_002880.3(RAF1):c.125C>T (p.Ala42Val) 343103 CA2259832 NM_002880.3:c.125C>T, LRG_413t1:c.125C>T, XM_005265355.1:c.125C>T, XM_005265357.1:c.125C>T, XM_005265358.3:c.-6C>T, XM_005265359.3:c.-6C>T, XM_005265360.1:c.125C>T, XM_011533974.1:c.125C>T, XM_011533975.1:c.-6C>T, NM_001354689.1:c.125C>T, NM_001354690.1:c.125C>T, NM_001354691.1:c.-6C>T, NM_001354692.1:c.-6C>T, NM_001354693.1:c.125C>T, NM_001354694.1:c.-6C>T, NM_001354695.1:c.-6C>T, NR_148940.1:n.540C>T, NR_148941.1:n.540C>T, NR_148942.1:n.540C>T, XM_011533974.3:c.125C>T, XM_017006966.1:c.125C>T, XR_001740227.1:n.456C>T, ENST00000251849.8:c.125C>T, ENST00000416093.1:c.125C>T, ENST00000423275.5:c.125C>T, ENST00000442415.6:c.125C>T, NC_000003.12:g.12618597G>A, CM000665.2:g.12618597G>A, NC_000003.11:g.12660096G>A, CM000665.1:g.12660096G>A, NC_000003.10:g.12635096G>A, NG_007467.1:g.50583C>T, LRG_413:g.50583C>T, NM_002880.3(RAF1):c.125C>T (p.Ala42Val) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.125C>T (p.Ala42Val) variant in the RAF1 gene is 0.026% (25/66738) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA2259832/MONDO:0021060/004 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692836 372481 A T NM_000277.2(PAH):c.1147C>T (p.Gln383Ter) 370701 CA16020949 NM_000277.2:c.1147C>T, NM_000277.1:c.1147C>T, XM_011538422.1:c.1090C>T, NM_001354304.1:c.1147C>T, NM_000277.3:c.1147C>T, ENST00000307000.7:c.1132C>T, ENST00000549247.6:n.906C>T, ENST00000551114.2:n.809C>T, ENST00000553106.5:c.1147C>T, ENST00000635477.1:n.251C>T, ENST00000635528.1:n.662C>T, NC_000012.12:g.102843698G>A, CM000674.2:g.102843698G>A, NC_000012.11:g.103237476G>A, CM000674.1:g.103237476G>A, NC_000012.10:g.101761606G>A, NG_008690.1:g.78905C>T, NG_008690.2:g.119713C>T, NM_000277.2(PAH):c.1147C>T (p.Gln383Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PM3 [MET], PP4 [MET] The c.1147C>T (p.Gln383Ter) variant in PAH is a nonsense variant predicted to undergo NMD, present in all biologically relevant transcripts, absent from all populations databases. It has been identified in a patient with classic PKU as homozygous, and in trans with a pathogenic variant (R408W), although defect in BH4 metabolism was not excluded in either patient. (PMID: 24350308, 22763404). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. 24350308, 22763404, 24350308, 22763404 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA16020949/MONDO:0009861/006 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89725043 372482 G A NM_000314.6(PTEN):c.320A>T (p.Asp107Val) 372481 CA16042748 NM_000314.6:c.320A>T, NM_000314.5:c.320A>T, NM_001304717.2:c.839A>T, NM_001304718.1:c.-431A>T, XM_006717926.2:c.275A>T, XM_011539981.1:c.320A>T, XM_011539982.1:c.224A>T, XR_945789.1:n.1032A>T, XR_945790.1:n.1032A>T, XR_945791.1:n.1032A>T, NM_000314.7:c.320A>T, NM_001304717.5:c.839A>T, NM_001304718.2:c.-431A>T, ENST00000371953.7:c.320A>T, ENST00000498703.1:n.146A>T, ENST00000610634.1:c.218A>T, NC_000010.11:g.87933079A>T, CM000672.2:g.87933079A>T, NC_000010.10:g.89692836A>T, CM000672.1:g.89692836A>T, NC_000010.9:g.89682816A>T, NG_007466.2:g.74641A>T, LRG_311:g.74641A>T, NM_000314.6(PTEN):c.320A>T (p.Asp107Val) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PM6 [MET], PVS1 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [MET], PP4 [Unmet], BS2 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS4-Moderate [MET], PS1 [Unmet], PS3 [MET], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], BS3 [Unmet] PTEN c.320A>T (p.Asp107Val) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type. (PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 25418537)PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28526761, PMID 23886400, internal laboratory contributor SCV000490750.2)PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 28526761, PMID 23886400, internal laboratory contributor SCV000490750.2)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 25418537, 23886400, 28526761, 25418537, 23886400, 28526761, 29706350, 29785012, 25418537, 23886400, 28526761 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA16042748/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763744 375406 T G NM_000314.6(PTEN):c.1027-1G>A 372482 CA16042723 NM_000314.6:c.1027-1G>A, NM_000314.5:c.1027-1G>A, NM_001304717.2:c.1546-1G>A, NM_001304718.1:c.436-1G>A, XM_006717926.2:c.982-1G>A, XM_011539982.1:c.931-1G>A, XR_945791.1:n.1597-1G>A, NM_000314.7:c.1027-1G>A, NM_001304717.5:c.1546-1G>A, NM_001304718.2:c.436-1G>A, ENST00000371953.7:c.1027-1G>A, NC_000010.11:g.87965286G>A, CM000672.2:g.87965286G>A, NC_000010.10:g.89725043G>A, CM000672.1:g.89725043G>A, NC_000010.9:g.89715023G>A, NG_007466.2:g.106848G>A, LRG_311:g.106848G>A, NM_000314.6(PTEN):c.1027-1G>A PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM6 [MET], PM2 [MET], PVS1 [MET], PP2 [Unmet], PP4 [Unmet], PP1 [Unmet], BS2 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS2 [Unmet], PS1 [Unmet], PS4 [Unmet], PS3 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet] PTEN c.1027-1G>A (IVS8-1G>A) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor SCV000490754.2) 20962022, 20962022, 27477328, 20962022 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA16042723/MONDO:0017623/003 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692904 375958 C G NM_004004.5(GJB2):c.-22-2A>C 375406 CA6904346 NM_004004.5:c.-22-2A>C, NC_000013.11:g.20189605T>G, CM000675.2:g.20189605T>G, NC_000013.10:g.20763744T>G, CM000675.1:g.20763744T>G, NC_000013.9:g.19661744T>G, NG_008358.1:g.8371A>C, XM_011535049.1:c.-22-2A>C, XM_011535049.2:c.-22-2A>C, NM_004004.6:c.-22-2A>C, ENST00000382844.1:c.-24A>C, ENST00000382848.4:c.-22-2A>C, NM_004004.5(GJB2):c.-22-2A>C GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Uncertain Significance PS3-Supporting [MET], PP1-Moderate [MET], PM2 [Unmet], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], PM3-Supporting [MET], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BS1 [MET], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] The filtering allele frequency of the c.-22-2A>C variant in the GJB2 gene is 0.35% for Ashkenazi Jewish chromosomes in the Genome Aggregation Database (46/10134 with 95% CI), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants (BS1). However, the c.-22-2A>C variant in the GJB2 gene has been detected in 2 patients with hearing loss in trans with the pathogenic c.35delG variant (PM3_S; PMID: 25401782, 24039984). This variant has been reported to segregate with hearing loss in at least 2 family members (PP1_M; PMID: 24039984). It was also identified in the heterozygous state without a second variant in 4 individuals with hearing loss, and in the biallelic state (with 35delG) in one individual with reportedly normal hearing (GeneDx, ARUP, unpublished data). RNA analysis showed that patients with the -22-2A>C variant express a novel GJB2 transcript with a slightly longer 5’UTR but otherwise normal coding region. The alternate transcript was shown to have reduced expression but it is not clear if the lower expression is sufficient to lead to a phenotype (PS3_Supporting; PMID: 24039984). In summary, due to its high allele frequency, insufficient case observations and insufficient functional evidence, this variant has been classified as uncertain clinical significance for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Supporting, PP1_Moderate, PS3_Supporting, BS1 24039984, 24039984, 25401782, 24039984, 25401782, 24039984, 24039984 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-10-25 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6904346/MONDO:0019497/005 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 10 89692993 375959 G T NM_000314.6(PTEN):c.388C>G (p.Arg130Gly) 375958 CA16602437 NM_000314.6:c.388C>G, NC_000010.11:g.87933147C>G, CM000672.2:g.87933147C>G, NC_000010.10:g.89692904C>G, CM000672.1:g.89692904C>G, NC_000010.9:g.89682884C>G, NG_007466.2:g.74709C>G, LRG_311:g.74709C>G, NM_000314.5:c.388C>G, NM_001304717.2:c.907C>G, NM_001304718.1:c.-363C>G, XM_006717926.2:c.343C>G, XM_011539981.1:c.388C>G, XM_011539982.1:c.292C>G, XR_945789.1:n.1100C>G, XR_945790.1:n.1100C>G, XR_945791.1:n.1100C>G, NM_000314.7:c.388C>G, NM_001304717.5:c.907C>G, NM_001304718.2:c.-363C>G, ENST00000371953.7:c.388C>G, ENST00000498703.1:n.214C>G, ENST00000610634.1:c.286C>G, NM_000314.6(PTEN):c.388C>G (p.Arg130Gly) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [MET], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM4 [Unmet], PM1 [MET], PM5 [MET] PTEN c.388C>G (p.Arg130Gly) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 10866302, PMID 21828076, PMID 29706350)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 7829, SCV000840465.2).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 10866302, 29706350, 29785012, 21828076, 19457929, 20926450, 21659347, 24778394, 19457929, 20926450, 25669429 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA16602437/MONDO:0017623/003 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 4 Uncertain Significance 21 36231783 376018 G A NM_000314.6(PTEN):c.477G>T (p.Arg159Ser) 375959 CA16602438 NM_000314.6:c.477G>T, NC_000010.11:g.87933236G>T, CM000672.2:g.87933236G>T, NC_000010.10:g.89692993G>T, CM000672.1:g.89692993G>T, NC_000010.9:g.89682973G>T, NG_007466.2:g.74798G>T, LRG_311:g.74798G>T, NM_000314.5:c.477G>T, NM_001304717.2:c.996G>T, NM_001304718.1:c.-274G>T, XM_006717926.2:c.432G>T, XM_011539981.1:c.477G>T, XM_011539982.1:c.381G>T, XR_945789.1:n.1189G>T, XR_945790.1:n.1189G>T, XR_945791.1:n.1189G>T, NM_000314.7:c.477G>T, NM_001304717.5:c.996G>T, NM_001304718.2:c.-274G>T, ENST00000371953.7:c.477G>T, ENST00000498703.1:n.303G>T, ENST00000610634.1:c.375G>T, NM_000314.6(PTEN):c.477G>T (p.Arg159Ser) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [MET], PS4 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.477G>T (p.Arg159Ser) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. 29617666, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA16602438/MONDO:0017623/003 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89717673 376510 G A NM_001754.4(RUNX1):c.601C>T (p.Arg201Ter) 376018 CA16602487 NM_001754.4:c.601C>T, NC_000021.9:g.34859486G>A, CM000683.2:g.34859486G>A, NC_000021.8:g.36231783G>A, CM000683.1:g.36231783G>A, NC_000021.7:g.35153653G>A, NG_011402.2:g.1130226C>T, LRG_482:g.1130226C>T, NM_001001890.2:c.520C>T, NM_001122607.1:c.520C>T, LRG_482t1:c.601C>T, XM_005261068.3:c.565C>T, XM_005261069.3:c.601C>T, XM_011529766.1:c.601C>T, XM_011529767.1:c.562C>T, XM_011529768.1:c.562C>T, XM_011529770.1:c.601C>T, XR_937576.1:n.780C>T, XM_005261069.4:c.601C>T, XM_011529766.2:c.601C>T, XM_011529767.2:c.562C>T, XM_011529768.2:c.562C>T, XM_011529770.2:c.601C>T, XM_017028487.1:c.448C>T, XR_937576.2:n.827C>T, ENST00000300305.7:c.601C>T, ENST00000344691.8:c.520C>T, ENST00000358356.9:c.520C>T, ENST00000399237.6:c.565C>T, ENST00000399240.5:c.520C>T, ENST00000437180.5:c.601C>T, ENST00000467577.1:n.93C>T, ENST00000482318.5:c.*191C>T, NM_001754.4(RUNX1):c.601C>T (p.Arg201Ter) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [MET], PM5 [Unmet], PM1 [Unmet], PM4 [Unmet], BS3 [Unmet], BS4 [Unmet], BS1 [Unmet], BP7 [Unmet], PP1-Strong [MET], PP3 [Unmet], PVS1 [MET], PM2 [MET], PM6 [Unmet] The NM_001754.4:c.601C>T (p.Arg201Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMIDs: 10508512; 19387465; 20549580; 28513614). The variant was found to co-segregate with disease in multiple affected family members, with 14 meioses observed in across 4 families (PP1_Strong; PMID: 10508512; 19387465; 20549580; 28513614). The variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4, PP1_Strong, PM2. 10508512, 28513614, 20549580, 19387465, 10508512, 28513614, 20549580, 19387465, 10508512, 28513614, 20549580, 19387465 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA16602487/MONDO:0011071/008 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 12 103288576 376937 T G NM_000314.6(PTEN):c.698G>A (p.Arg233Gln) 376510 CA060404 NM_000314.6:c.698G>A, NC_000010.11:g.87957916G>A, CM000672.2:g.87957916G>A, NC_000010.10:g.89717673G>A, CM000672.1:g.89717673G>A, NC_000010.9:g.89707653G>A, NG_007466.2:g.99478G>A, LRG_311:g.99478G>A, NM_000314.5:c.698G>A, NM_001304717.2:c.1217G>A, NM_001304718.1:c.107G>A, XM_006717926.2:c.653G>A, XM_011539981.1:c.698G>A, XM_011539982.1:c.602G>A, XR_945791.1:n.1268G>A, NM_000314.7:c.698G>A, NM_001304717.5:c.1217G>A, NM_001304718.2:c.107G>A, ENST00000371953.7:c.698G>A, ENST00000472832.2:n.125G>A, NM_000314.6(PTEN):c.698G>A (p.Arg233Gln) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP2 [MET], PP3 [Unmet], PP1 [Unmet], BA1 [Unmet], BS3-Supporting [MET], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] PTEN c.698G>A (p.R233Q) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) 27147599, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA060404/MONDO:0017623/003 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 19 4099305 378108 G A NM_000277.2(PAH):c.289A>C (p.Ile97Leu) 376937 CA6748987 NM_000277.2:c.289A>C, NC_000012.12:g.102894798T>G, CM000674.2:g.102894798T>G, NC_000012.11:g.103288576T>G, CM000674.1:g.103288576T>G, NC_000012.10:g.101812706T>G, NG_008690.1:g.27805A>C, NG_008690.2:g.68613A>C, NM_000277.1:c.289A>C, XM_011538422.1:c.289A>C, NM_001354304.1:c.289A>C, XM_017019370.2:c.289A>C, NM_000277.3:c.289A>C, ENST00000307000.7:c.274A>C, ENST00000546844.1:c.289A>C, ENST00000548928.1:n.211A>C, ENST00000549111.5:n.385A>C, ENST00000550978.6:n.273A>C, ENST00000551337.5:c.289A>C, ENST00000551988.5:n.378A>C, ENST00000553106.5:c.289A>C, NM_000277.2(PAH):c.289A>C (p.Ile97Leu) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Uncertain Significance PM2 [Unmet], PP4 [MET], BP4 [MET] PAH-specific ACMG/AMP criteria applied: BP4: Tolerated in SIFT, benign in Polyphen-2, Polymorphism in MutationTaster. REVEL=0.511; PP4: Seen in patient with mild HPA (PMID:17627389). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BP4, PP4). 17627389 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-07 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6748987/MONDO:0009861/006 0.0028 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 19 4117480 378913 C T NM_030662.3(MAP2K2):c.813C>T (p.Asp271=) 378108 CA9090826 NM_030662.3:c.813C>T, LRG_750t1:c.813C>T, XM_006722799.2:c.705+1712C>T, XM_011528133.1:c.243C>T, XM_017026989.1:c.813C>T, XM_017026990.1:c.705+1712C>T, ENST00000262948.9:c.813C>T, ENST00000394867.8:c.522C>T, ENST00000593364.5:n.760C>T, ENST00000595715.1:n.628C>T, ENST00000597263.5:n.169+1712C>T, ENST00000599021.1:n.29+1712C>T, ENST00000600584.5:n.1373C>T, ENST00000601786.5:n.1114C>T, NC_000019.10:g.4099307G>A, CM000681.2:g.4099307G>A, NC_000019.9:g.4099305G>A, CM000681.1:g.4099305G>A, NC_000019.8:g.4050305G>A, NG_007996.1:g.29822C>T, LRG_750:g.29822C>T, NM_030662.3(MAP2K2):c.813C>T (p.Asp271=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.813C>T (p.Asp271=) variant in the MAP2K2 gene is 0.0045% (1/7096) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA9090826/MONDO:0021060/004 0.0002 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 10 89624270 404147 G A NM_030662.3(MAP2K2):c.240G>A (p.Ala80=) 378913 CA9091070 NM_030662.3:c.240G>A, NC_000019.10:g.4117482C>T, CM000681.2:g.4117482C>T, NC_000019.9:g.4117480C>T, CM000681.1:g.4117480C>T, NC_000019.8:g.4068480C>T, NG_007996.1:g.11647G>A, LRG_750:g.11647G>A, LRG_750t1:c.240G>A, XM_006722799.2:c.240G>A, XM_017026989.1:c.240G>A, XM_017026990.1:c.240G>A, XM_017026991.1:c.240G>A, ENST00000262948.9:c.240G>A, ENST00000394867.8:c.-52G>A, ENST00000599345.1:n.437G>A, NM_030662.3(MAP2K2):c.240G>A (p.Ala80=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.240G>A (p.Ala80=) variant in the MAP2K2 gene is 0.0284% (9/16506) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA9091070/MONDO:0021060/004 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68862107 406663 G A NM_000314.6(PTEN):c.44G>A (p.Arg15Lys) 404147 CA16613142 NM_000314.6:c.44G>A, NM_000314.5:c.44G>A, NM_001304717.2:c.563G>A, NM_001304718.1:c.-662G>A, XM_006717926.2:c.44G>A, XM_011539981.1:c.44G>A, XR_945789.1:n.756G>A, XR_945790.1:n.756G>A, XR_945791.1:n.756G>A, NM_000314.7:c.44G>A, NM_001304717.5:c.563G>A, NM_001304718.2:c.-662G>A, ENST00000371953.7:c.44G>A, ENST00000462694.1:n.46G>A, ENST00000487939.1:n.65G>A, ENST00000610634.1:c.-59G>A, ENST00000618586.1:n.13G>A, NC_000010.11:g.87864513G>A, CM000672.2:g.87864513G>A, NC_000010.10:g.89624270G>A, CM000672.1:g.89624270G>A, NC_000010.9:g.89614250G>A, NG_007466.2:g.6075G>A, LRG_311:g.6075G>A, NG_033079.1:g.3925C>T, NM_000314.6(PTEN):c.44G>A (p.Arg15Lys) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Uncertain Significance PM2 [MET], PP2 [MET], PS3-Supporting [MET] PTEN c.44G>A (p.R15K) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 25875300) PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-01-03 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA16613142/MONDO:0017623/003 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 21 36259139 409822 C G NM_004360.4(CDH1):c.2195G>A (p.Arg732Gln) 406663 CA16615410 NM_004360.4:c.2195G>A, NC_000016.10:g.68828204G>A, CM000678.2:g.68828204G>A, NC_000016.9:g.68862107G>A, CM000678.1:g.68862107G>A, NC_000016.8:g.67419608G>A, NG_008021.1:g.95913G>A, LRG_301:g.95913G>A, NM_004360.3:c.2195G>A, LRG_301t1:c.2195G>A, XM_011523488.1:c.1460G>A, XM_011523489.1:c.1460G>A, NM_001317184.1:c.2012G>A, NM_001317185.1:c.647G>A, NM_001317186.1:c.230G>A, ENST00000261769.9:c.2195G>A, ENST00000422392.6:c.2012G>A, ENST00000562118.1:n.413G>A, ENST00000562836.5:n.2266G>A, ENST00000566510.5:c.*861G>A, ENST00000566612.5:c.*435G>A, ENST00000611625.4:c.2258G>A, ENST00000612417.4:c.1853+1650G>A, ENST00000621016.4:c.1866-5999G>A, NM_004360.4(CDH1):c.2195G>A (p.Arg732Gln) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Likely Pathogenic BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PVS1 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [MET], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS4-Moderate [MET], PS3 [MET], PS1 [Unmet], PS2 [Unmet] The c.2195G>A (p.Arg732Gln) variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant is predicted to affect splicing by at least 3 in silico splicing predictors in agreement (PP3). Additionally, there is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 17545690 15235021). This variant has also been reported in at least 2 families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17545690 15235021). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2, PP3, PS3, PS4_Moderate. 17545690, 17545690, 15235021, 17545690, 15235021, 26580448 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA16615410/MONDO:0007648/007 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36206814 415832 C T NM_001754.4(RUNX1):c.351+1G>C 409822 CA16616270 NM_001754.4:c.351+1G>C, NC_000021.9:g.34886842C>G, CM000683.2:g.34886842C>G, NC_000021.8:g.36259139C>G, CM000683.1:g.36259139C>G, NC_000021.7:g.35181009C>G, NG_011402.2:g.1102870G>C, LRG_482:g.1102870G>C, NM_001001890.2:c.270+1G>C, NM_001122607.1:c.270+1G>C, LRG_482t1:c.351+1G>C, XM_005261068.3:c.315+1G>C, XM_005261069.3:c.351+1G>C, XM_011529766.1:c.351+1G>C, XM_011529767.1:c.312+1G>C, XM_011529768.1:c.312+1G>C, XM_011529770.1:c.351+1G>C, XR_937576.1:n.530+1G>C, XM_005261069.4:c.351+1G>C, XM_011529766.2:c.351+1G>C, XM_011529767.2:c.312+1G>C, XM_011529768.2:c.312+1G>C, XM_011529770.2:c.351+1G>C, XM_017028487.1:c.198+1G>C, XR_937576.2:n.577+1G>C, ENST00000300305.7:c.351+1G>C, ENST00000344691.8:c.270+1G>C, ENST00000358356.9:c.270+1G>C, ENST00000399237.6:c.315+1G>C, ENST00000399240.5:c.270+1G>C, ENST00000437180.5:c.351+1G>C, ENST00000455571.5:c.312+1G>C, ENST00000482318.5:c.59-6129G>C, NM_001754.4(RUNX1):c.351+1G>C RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], PP3 [Unmet], PP1 [Unmet], PVS1 [MET], PM2 [MET], PM6 [Unmet] The NM_001754.4(RUNX1):c.351+1G>C variant is a canonical splice site variant that is predicted to introduce a frameshift and a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA16616270/MONDO:0011071/008 0.025 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 1, 0, 0] 1 Uncertain Significance 7 140500166 417225 T C NM_001754.4(RUNX1):c.698G>A (p.Arg233His) 415832 CA10014373 NM_001754.4:c.698G>A, NM_001001890.2:c.617G>A, NM_001122607.1:c.617G>A, LRG_482t1:c.698G>A, XM_005261068.3:c.662G>A, XM_005261069.3:c.613+24957G>A, XM_011529766.1:c.698G>A, XM_011529767.1:c.659G>A, XM_011529768.1:c.574+24957G>A, XM_011529770.1:c.698G>A, XR_937576.1:n.877G>A, XM_005261069.4:c.613+24957G>A, XM_011529766.2:c.698G>A, XM_011529767.2:c.659G>A, XM_011529768.2:c.574+24957G>A, XM_011529770.2:c.698G>A, XM_017028487.1:c.545G>A, XR_937576.2:n.924G>A, ENST00000300305.7:c.698G>A, ENST00000344691.8:c.617G>A, ENST00000358356.9:c.617G>A, ENST00000399237.6:c.662G>A, ENST00000399240.5:c.532+24957G>A, ENST00000437180.5:c.698G>A, ENST00000469087.1:n.234G>A, ENST00000482318.5:c.*288G>A, NC_000021.9:g.34834517C>T, CM000683.2:g.34834517C>T, NC_000021.8:g.36206814C>T, CM000683.1:g.36206814C>T, NC_000021.7:g.35128684C>T, NG_011402.2:g.1155195G>A, LRG_482:g.1155195G>A, NM_001754.4(RUNX1):c.698G>A (p.Arg233His) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Benign BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [MET], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.698G>A (p.Arg233His) variant has a MAF of 0.00142 (0.142%, 34/23,970 alleles) in the African subpopulation of the gnomAD cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). We allow a variant to reach a likely benign classification based on BS1 alone if there is no contradictory evidence supporting pathogenicity. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014373/MONDO:0011071/008 0.0028 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 0, 0] 2 Uncertain Significance 21 36252865 417961 C T NM_004333.4(BRAF):c.976A>G (p.Ile326Val) 417225 CA4516861 NM_004333.4:c.976A>G, LRG_299t1:c.976A>G, XM_005250045.1:c.976A>G, XM_005250046.1:c.976A>G, XM_011516529.1:c.976A>G, XM_011516530.1:c.976A>G, XR_242190.1:n.984A>G, XR_927520.1:n.984A>G, XR_927521.1:n.984A>G, XR_927522.1:n.984A>G, XR_927523.1:n.984A>G, NM_001354609.1:c.976A>G, NM_004333.5:c.976A>G, NR_148928.1:n.1281A>G, XM_017012558.1:c.976A>G, XM_017012559.1:c.976A>G, XR_001744857.1:n.984A>G, XR_001744858.1:n.984A>G, ENST00000288602.10:c.976A>G, ENST00000497784.1:n.1011A>G, NC_000007.14:g.140800366T>C, CM000669.2:g.140800366T>C, NC_000007.13:g.140500166T>C, CM000669.1:g.140500166T>C, NC_000007.12:g.140146635T>C, NG_007873.3:g.129399A>G, LRG_299:g.129399A>G, NM_004333.4(BRAF):c.976A>G (p.Ile326Val) BRAF RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1772A>G (p.Asn591Ser) variant in the SOS1 gene is 0.054% (11/11524) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA4516861/MONDO:0021060/004 0.8999 Likely Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68862157 418841 C T NM_001754.4(RUNX1):c.497G>A (p.Arg166Gln) 417961 CA16616941 NM_001754.4:c.497G>A, NC_000021.9:g.34880568C>T, CM000683.2:g.34880568C>T, NC_000021.8:g.36252865C>T, CM000683.1:g.36252865C>T, NC_000021.7:g.35174735C>T, NG_011402.2:g.1109144G>A, LRG_482:g.1109144G>A, NM_001001890.2:c.416G>A, NM_001122607.1:c.416G>A, LRG_482t1:c.497G>A, XM_005261068.3:c.461G>A, XM_005261069.3:c.497G>A, XM_011529766.1:c.497G>A, XM_011529767.1:c.458G>A, XM_011529768.1:c.458G>A, XM_011529770.1:c.497G>A, XR_937576.1:n.676G>A, XM_005261069.4:c.497G>A, XM_011529766.2:c.497G>A, XM_011529767.2:c.458G>A, XM_011529768.2:c.458G>A, XM_011529770.2:c.497G>A, XM_017028487.1:c.344G>A, XR_937576.2:n.723G>A, ENST00000300305.7:c.497G>A, ENST00000344691.8:c.416G>A, ENST00000358356.9:c.416G>A, ENST00000399237.6:c.461G>A, ENST00000399240.5:c.416G>A, ENST00000437180.5:c.497G>A, ENST00000482318.5:c.*87G>A, NM_001754.4(RUNX1):c.497G>A (p.Arg166Gln) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS4-Moderate [MET], PS1 [Unmet], PS3 [MET], PM5 [Unmet], PM4 [Unmet], PM1 [MET], BP7 [Unmet], BS3 [Unmet], BS4 [Unmet], BS1 [Unmet], PM6-Supporting [MET], PP3 [MET], PP1 [MET], PM2 [MET], PVS1 [Unmet] Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.497G>A (p.Arg166Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 11830488, 25840971, 23848403). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 10508512, 28960434, 26175287). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It has a REVEL score >0.75 (0.962) (PP3). There are two unrelated probands meeting at least one of the RUNX1- phenotypic criteria with assumed de novo occurrence (without confirmation of maternity and paternity) (PM6_ Supporting; PMID: 8960434, 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 10508512). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM1, PS4_Moderate, PM2, PP3, PM6_Supporting, PP1. 10508512, 28960434, 26175287, 11830488, 25840971, 23848403, 10508512, 28960434, 26175287, 10508512 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA16616941/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89712021 427623 G C NM_004360.4(CDH1):c.2245C>T (p.Arg749Trp) 418841 CA8130235 NM_004360.4:c.2245C>T, NC_000016.10:g.68828254C>T, CM000678.2:g.68828254C>T, NC_000016.9:g.68862157C>T, CM000678.1:g.68862157C>T, NC_000016.8:g.67419658C>T, NG_008021.1:g.95963C>T, LRG_301:g.95963C>T, NM_004360.3:c.2245C>T, LRG_301t1:c.2245C>T, XM_011523488.1:c.1510C>T, XM_011523489.1:c.1510C>T, NM_001317184.1:c.2062C>T, NM_001317185.1:c.697C>T, NM_001317186.1:c.280C>T, ENST00000261769.9:c.2245C>T, ENST00000422392.6:c.2062C>T, ENST00000562118.1:n.463C>T, ENST00000562836.5:n.2316C>T, ENST00000566510.5:c.*911C>T, ENST00000566612.5:c.*485C>T, ENST00000611625.4:c.2308C>T, ENST00000612417.4:c.1853+1700C>T, ENST00000621016.4:c.1866-5949C>T, NM_004360.4(CDH1):c.2245C>T (p.Arg749Trp) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Uncertain Significance BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet], PVS1 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet] The c.2245C>T (p.Arg749Trp) variant is present in <1/100,000 alleles in the ExAC cohort (PM2; http://exac.broadinstitute.org). There is no other supporting data that meet criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: PM2. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA8130235/MONDO:0007648/007 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89711893 428206 C CA NM_000314.6(PTEN):c.634+5G>C 427623 CA645509438 NM_000314.6:c.634+5G>C, NM_000314.5:c.634+5G>C, NM_001304717.2:c.1153+5G>C, NM_001304718.1:c.43+5G>C, XM_006717926.2:c.589+5G>C, XM_011539981.1:c.634+5G>C, XM_011539982.1:c.538+5G>C, XR_945791.1:n.1205-5589G>C, NM_000314.7:c.634+5G>C, NM_001304717.5:c.1153+5G>C, NM_001304718.2:c.43+5G>C, ENST00000371953.7:c.634+5G>C, ENST00000472832.2:n.61+5G>C, NC_000010.11:g.87952264G>C, CM000672.2:g.87952264G>C, NC_000010.10:g.89712021G>C, CM000672.1:g.89712021G>C, NC_000010.9:g.89702001G>C, NG_007466.2:g.93826G>C, LRG_311:g.93826G>C, NM_000314.6(PTEN):c.634+5G>C PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], BS2 [Unmet], PS4-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [MET], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet] PTEN c.634+5G>C (IVS6+5G>C) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: RNA, mini-gene, or other assay shows impact on splicing. (PMID 28677221)PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221) 21659347, 28677221, 28677221 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA645509438/MONDO:0017623/003 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692957 428216 GG A NM_000314.6(PTEN):c.512dup (p.Arg172Glufs) 428206 CA645369422 NM_000314.6:c.512dup, NM_000314.5:c.512dup, NM_001304717.2:c.1031dup, NM_001304718.1:c.-80dup, XM_006717926.2:c.467dup, XM_011539981.1:c.512dup, XM_011539982.1:c.416dup, XR_945789.1:n.1383dup, XR_945790.1:n.1500dup, XR_945791.1:n.1205-5716dup, NM_000314.7:c.512dup, NM_001304717.5:c.1031dup, NM_001304718.2:c.-80dup, ENST00000371953.7:c.512dup, NC_000010.11:g.87952137dup, CM000672.2:g.87952137dup, NC_000010.10:g.89711894dup, CM000672.1:g.89711894dup, NC_000010.9:g.89701874dup, NG_007466.2:g.93699dup, LRG_311:g.93699dup, NM_000314.6(PTEN):c.512dup (p.Arg172Glufs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], BS2 [Unmet], PS4-Supporting [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet] PTEN c.512dup (p.R172Efs) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 17526801) 27477328, 22261759, 25669429, 21659347, 17526801, 21190448, 20962022, 21956414, 21194675, 20600018 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA645369422/MONDO:0017623/003 0.4999 VUS Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89692782 428271 C CT NM_000314.6(PTEN):c.441_442delGGinsA (p.Ala148Hisfs) 428216 CA645369482 NM_000314.6:c.441_442delGGinsA, NC_000010.11:g.87933200_87933201delinsA, CM000672.2:g.87933200_87933201delinsA, NC_000010.10:g.89692957_89692958delinsA, CM000672.1:g.89692957_89692958delinsA, NC_000010.9:g.89682937_89682938delinsA, NG_007466.2:g.74762_74763delinsA, LRG_311:g.74762_74763delinsA, NM_000314.5:c.441_442delinsA, NM_000314.6:c.441_442delinsA, NM_001304717.2:c.960_961delinsA, NM_001304718.1:c.-310_-309delinsA, XM_006717926.2:c.396_397delinsA, XM_011539981.1:c.441_442delinsA, XM_011539982.1:c.345_346delinsA, XR_945789.1:n.1153_1154delinsA, XR_945790.1:n.1153_1154delinsA, XR_945791.1:n.1153_1154delinsA, NM_000314.7:c.441_442delinsA, NM_001304717.5:c.960_961delinsA, NM_001304718.2:c.-310_-309delinsA, ENST00000371953.7:c.441_442delinsA, ENST00000498703.1:n.267_268delinsA, ENST00000610634.1:c.339_340delinsA, NM_000314.6(PTEN):c.441_442delGGinsA (p.Ala148Hisfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [MET], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet] PTEN c.441_442delGGinsA (p.Ala148Hisfs) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). 22261759, 27477328, 10400993, 25669429 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA645369482/MONDO:0017623/003 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 89720733 428274 TATGTGATCAAGAAATC G NM_000314.6(PTEN):c.270dup (p.Glu91Terfs) 428271 CA645369474 NM_000314.6:c.270dup, NM_000314.5:c.270dup, NM_001304717.2:c.789dup, NM_001304718.1:c.-481dup, XM_006717926.2:c.225dup, XM_011539981.1:c.270dup, XM_011539982.1:c.174dup, XR_945789.1:n.982dup, XR_945790.1:n.982dup, XR_945791.1:n.982dup, NM_000314.7:c.270dup, NM_001304717.5:c.789dup, NM_001304718.2:c.-481dup, ENST00000371953.7:c.270dup, ENST00000498703.1:n.96dup, ENST00000610634.1:c.168dup, NC_000010.11:g.87933029dup, CM000672.2:g.87933029dup, NC_000010.10:g.89692786dup, CM000672.1:g.89692786dup, NC_000010.9:g.89682766dup, NG_007466.2:g.74591dup, LRG_311:g.74591dup, NM_000314.6(PTEN):c.270dup (p.Glu91Terfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PVS1 [MET], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PS1 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet] PTEN c.270dup (p.Glu91Terfs) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-11-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA645369474/MONDO:0017623/003 0.4999 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36252995 429813 C G NM_000314.6(PTEN):c.884_900del17insG (p.Leu295Argfs) 428274 CA645369469 NM_000314.6:c.884_900del17insG, NM_000314.5:c.884_900delinsG, NM_000314.6:c.884_900delinsG, NM_001304717.2:c.1403_1419delinsG, NM_001304718.1:c.293_309delinsG, XM_006717926.2:c.839_855delinsG, XM_011539981.1:c.884_900delinsG, XM_011539982.1:c.788_804delinsG, XR_945791.1:n.1454_1470delinsG, NM_000314.7:c.884_900delinsG, NM_001304717.5:c.1403_1419delinsG, NM_001304718.2:c.293_309delinsG, ENST00000371953.7:c.884_900delinsG, ENST00000472832.2:n.311_327delinsG, NC_000010.11:g.87960976_87960992delinsG, CM000672.2:g.87960976_87960992delinsG, NC_000010.10:g.89720733_89720749delinsG, CM000672.1:g.89720733_89720749delinsG, NC_000010.9:g.89710713_89710729delinsG, NG_007466.2:g.102538_102554delinsG, LRG_311:g.102538_102554delinsG, NM_000314.6(PTEN):c.884_900del17insG (p.Leu295Argfs) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PVS1 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP2 [Unmet], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet] PTEN c.884_900del17insG (p.Leu295Argfs) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf 2018-11-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA645369469/MONDO:0017623/003 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 1, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 112920006 436446 A G NM_001754.4(RUNX1):c.367G>C (p.Asp123His) 429813 CA10014524 NM_001754.4:c.367G>C, NM_001001890.2:c.286G>C, NM_001122607.1:c.286G>C, LRG_482t1:c.367G>C, XM_005261068.3:c.331G>C, XM_005261069.3:c.367G>C, XM_011529766.1:c.367G>C, XM_011529767.1:c.328G>C, XM_011529768.1:c.328G>C, XM_011529770.1:c.367G>C, XR_937576.1:n.546G>C, XM_005261069.4:c.367G>C, XM_011529766.2:c.367G>C, XM_011529767.2:c.328G>C, XM_011529768.2:c.328G>C, XM_011529770.2:c.367G>C, XM_017028487.1:c.214G>C, XR_937576.2:n.593G>C, ENST00000300305.7:c.367G>C, ENST00000344691.8:c.286G>C, ENST00000358356.9:c.286G>C, ENST00000399237.6:c.331G>C, ENST00000399240.5:c.286G>C, ENST00000437180.5:c.367G>C, ENST00000455571.5:c.328G>C, ENST00000482318.5:c.74G>C, NC_000021.9:g.34880698C>G, CM000683.2:g.34880698C>G, NC_000021.8:g.36252995C>G, CM000683.1:g.36252995C>G, NC_000021.7:g.35174865C>G, NG_011402.2:g.1109014G>C, LRG_482:g.1109014G>C, NM_001754.4(RUNX1):c.367G>C (p.Asp123His) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PM1-Supporting [MET], PM5 [Unmet], PM4 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [MET], PP1 [Unmet], PS4-Supporting [MET], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.367G>C (p.Asp123His) missense variant has a REVEL score >0.75 (0.943) (PP3). This variant affects one of the other residues (AA 105-204; not established as a hot spot by the MM-VCEP) within the RHD PM1_Supporting). The variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 18723428). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_Supporting, PS4_Supporting. 18723428, 18723428, 18723428 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014524/MONDO:0011071/008 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 1, 1, 0] 2 Uncertain Significance 21 36164618 436611 C T NM_002834.4(PTPN11):c.1221A>G (p.Gly407=) 436446 CA6798737 NM_002834.4:c.1221A>G, NM_002834.3:c.1221A>G, LRG_614t1:c.1221A>G, NM_080601.1:c.1221A>G, XM_006719526.1:c.1221A>G, XM_006719527.1:c.1107A>G, XM_011538613.1:c.1218A>G, NM_001330437.1:c.1221A>G, NM_080601.2:c.1221A>G, XM_011538613.2:c.1218A>G, XM_017019722.1:c.1218A>G, ENST00000351677.6:c.1221A>G, ENST00000392597.5:c.1221A>G, ENST00000635625.1:n.1221A>G, ENST00000635652.1:n.213A>G, NC_000012.12:g.112482202A>G, CM000674.2:g.112482202A>G, NC_000012.11:g.112920006A>G, CM000674.1:g.112920006A>G, NC_000012.10:g.111404389A>G, NG_007459.1:g.68471A>G, LRG_614:g.68471A>G, NM_002834.4(PTPN11):c.1221A>G (p.Gly407=) PTPN11 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1221A>G (p.Gly407=) variant in the PTPN11 gene is 0.115% (27/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6798737/MONDO:0021060/004 0.3246 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 21 36253011 436616 C T NM_001754.4(RUNX1):c.1257G>A (p.Val419=) 436611 CA512341177 NM_001754.4:c.1257G>A, NC_000021.9:g.34792321C>T, CM000683.2:g.34792321C>T, NC_000021.8:g.36164618C>T, CM000683.1:g.36164618C>T, NC_000021.7:g.35086488C>T, NG_011402.2:g.1197391G>A, LRG_482:g.1197391G>A, NM_001001890.2:c.1176G>A, LRG_482t1:c.1257G>A, XM_005261068.3:c.1221G>A, XM_005261069.3:c.1065G>A, XM_011529766.1:c.1257G>A, XM_011529767.1:c.1218G>A, XM_011529768.1:c.1026G>A, XM_005261069.4:c.1065G>A, XM_011529766.2:c.1257G>A, XM_011529767.2:c.1218G>A, XM_011529768.2:c.1026G>A, XM_017028487.1:c.1104G>A, ENST00000300305.7:c.1257G>A, ENST00000344691.8:c.1176G>A, ENST00000399240.5:c.984G>A, ENST00000437180.5:c.1257G>A, ENST00000482318.5:c.*847G>A, NM_001754.4(RUNX1):c.1257G>A (p.Val419=) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], BP7 [Unmet], PP3 [Unmet], PP1 [Unmet], PM2 [Unmet], PVS1 [Unmet], PM6 [Unmet] Even though the NM_001754.4:c.1257G>A (p.Val419=) variant is predicted to create alternative splice acceptor sites, MES and SSF are not predicted to abolish any existing consensus sites and it is too far away from either end of the exon for a prediction regarding the affect on the consensus acceptor or donor sites. The allele Frequency of this variant in gnomAD is 0.00003. In summary, the clinical significance of this variant is uncertain (VUS). None of the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA512341177/MONDO:0011071/008 0.9986 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36259175 436617 A T NM_001754.4(RUNX1):c.352-1G>A 436616 CA410202793 NM_001754.4:c.352-1G>A, NM_001001890.2:c.271-1G>A, NM_001122607.1:c.271-1G>A, LRG_482t1:c.352-1G>A, XM_005261068.3:c.316-1G>A, XM_005261069.3:c.352-1G>A, XM_011529766.1:c.352-1G>A, XM_011529767.1:c.313-1G>A, XM_011529768.1:c.313-1G>A, XM_011529770.1:c.352-1G>A, XR_937576.1:n.531-1G>A, XM_005261069.4:c.352-1G>A, XM_011529766.2:c.352-1G>A, XM_011529767.2:c.313-1G>A, XM_011529768.2:c.313-1G>A, XM_011529770.2:c.352-1G>A, XM_017028487.1:c.199-1G>A, XR_937576.2:n.578-1G>A, ENST00000300305.7:c.352-1G>A, ENST00000344691.8:c.271-1G>A, ENST00000358356.9:c.271-1G>A, ENST00000399237.6:c.316-1G>A, ENST00000399240.5:c.271-1G>A, ENST00000437180.5:c.352-1G>A, ENST00000455571.5:c.313-1G>A, ENST00000482318.5:c.59-1G>A, NC_000021.9:g.34880714C>T, CM000683.2:g.34880714C>T, NC_000021.8:g.36253011C>T, CM000683.1:g.36253011C>T, NC_000021.7:g.35174881C>T, NG_011402.2:g.1108998G>A, LRG_482:g.1108998G>A, NM_001754.4(RUNX1):c.352-1G>A RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS3 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [MET], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [MET] The NM_001754.4:c.352-1G>A variant is a canonical splice site variant that is predicted to introduce a frameshift and premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 26175287). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2, PS4_Supporting, PP1. 26175287, 26175287, 26175287 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410202793/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 21 36259232 436618 C A NM_001754.4(RUNX1):c.316T>A (p.Trp106Arg) 436617 CA410203508 NM_001754.4:c.316T>A, NC_000021.9:g.34886878A>T, CM000683.2:g.34886878A>T, NC_000021.8:g.36259175A>T, CM000683.1:g.36259175A>T, NC_000021.7:g.35181045A>T, NG_011402.2:g.1102834T>A, LRG_482:g.1102834T>A, NM_001001890.2:c.235T>A, NM_001122607.1:c.235T>A, LRG_482t1:c.316T>A, XM_005261068.3:c.280T>A, XM_005261069.3:c.316T>A, XM_011529766.1:c.316T>A, XM_011529767.1:c.277T>A, XM_011529768.1:c.277T>A, XM_011529770.1:c.316T>A, XR_937576.1:n.495T>A, XM_005261069.4:c.316T>A, XM_011529766.2:c.316T>A, XM_011529767.2:c.277T>A, XM_011529768.2:c.277T>A, XM_011529770.2:c.316T>A, XM_017028487.1:c.163T>A, XR_937576.2:n.542T>A, ENST00000300305.7:c.316T>A, ENST00000344691.8:c.235T>A, ENST00000358356.9:c.235T>A, ENST00000399237.6:c.280T>A, ENST00000399240.5:c.235T>A, ENST00000437180.5:c.316T>A, ENST00000455571.5:c.277T>A, ENST00000482318.5:c.59-6165T>A, NM_001754.4(RUNX1):c.316T>A (p.Trp106Arg) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [MET], PS4 [Unmet], PM1-Supporting [MET], PM5 [Unmet], PM4 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], PP3 [MET], PP1 [Unmet], PVS1 [Unmet], PM2 [MET], PM6 [Unmet] The NM_001754.4:c.316T>A (p.Trp106Arg) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) AND data from secondary assay demonstrate altered DNA binding. (PS3; PMID: 25840971). This missense variant has a REVEL score >0.75 (0.976) (PP3). All patients reported in literature with this variant were not confirmed as germline variants (PMID: 21828118, PMID: 19282830, PMID: 25840971). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM2, PP3, PM1_supporting. 25840971 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410203508/MONDO:0011071/008 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246589 439228 T C NM_001754.4(RUNX1):c.259G>T (p.Gly87Cys) 436618 CA10014559 NM_001754.4:c.259G>T, NC_000021.9:g.34886935C>A, CM000683.2:g.34886935C>A, NC_000021.8:g.36259232C>A, CM000683.1:g.36259232C>A, NC_000021.7:g.35181102C>A, NG_011402.2:g.1102777G>T, LRG_482:g.1102777G>T, NM_001001890.2:c.178G>T, NM_001122607.1:c.178G>T, LRG_482t1:c.259G>T, XM_005261068.3:c.223G>T, XM_005261069.3:c.259G>T, XM_011529766.1:c.259G>T, XM_011529767.1:c.220G>T, XM_011529768.1:c.220G>T, XM_011529770.1:c.259G>T, XR_937576.1:n.438G>T, XM_005261069.4:c.259G>T, XM_011529766.2:c.259G>T, XM_011529767.2:c.220G>T, XM_011529768.2:c.220G>T, XM_011529770.2:c.259G>T, XM_017028487.1:c.106G>T, XR_937576.2:n.485G>T, ENST00000300305.7:c.259G>T, ENST00000344691.8:c.178G>T, ENST00000358356.9:c.178G>T, ENST00000399237.6:c.223G>T, ENST00000399240.5:c.178G>T, ENST00000437180.5:c.259G>T, ENST00000455571.5:c.220G>T, ENST00000482318.5:c.59-6222G>T, NM_001754.4(RUNX1):c.259G>T (p.Gly87Cys) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [MET], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.259G>T (p.Gly87Cys) variant is a missense variant has a REVEL score >0.75 (0.918) (PP3). AMR Subpopulation of 1000 Genomes Allele frequency 0.00144 with 1 allele out of 694 alleles. In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014559/MONDO:0011071/008 0.3246 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 10 73464800 444219 G A NM_000277.1:c.842+4A>G 439228 CA16020870 NM_000277.1:c.842+4A>G, NC_000012.12:g.102852811T>C, CM000674.2:g.102852811T>C, NC_000012.11:g.103246589T>C, CM000674.1:g.103246589T>C, NC_000012.10:g.101770719T>C, NG_008690.1:g.69792A>G, NG_008690.2:g.110600A>G, XM_011538422.1:c.842+4A>G, NM_000277.2:c.842+4A>G, NM_001354304.1:c.842+4A>G, NM_000277.3:c.842+4A>G, ENST00000307000.7:c.827+4A>G, ENST00000549247.6:n.601+4A>G, ENST00000553106.5:c.842+4A>G, ENST00000635477.1:n.3+4A>G PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET] PAH-specific ACMG/AMP criteria applied: PP3: HSF: Broken WT Donor Site, New Donor Site. MaxEnt: Broken WT Donor Site.; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4_Moderate: IVS7+4A>G seen in 2 PKU patients. BH4 deficiency was ruled out. Upgraded per ClinGen PAH EP. (PMID:21147011); PM3: Detected in trans with A300S, pathogenic in ClinVar (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM2, PP4_Moderate, PM3). 21147011, 21147011 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-12 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA16020870/MONDO:0009861/006 0.8999 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763044 447450 A C NM_022124.5(CDH23):c.2866G>A (p.Glu956Lys) 444219 CA5544361 NM_022124.5:c.2866G>A, NM_001171930.1:c.2866G>A, NM_001171931.1:c.2866G>A, XM_006717940.2:c.3061G>A, XM_006717942.2:c.2995G>A, XM_011540039.1:c.3061G>A, XM_011540040.1:c.3055G>A, XM_011540041.1:c.3001G>A, XM_011540042.1:c.3061G>A, XM_011540043.1:c.3061G>A, XM_011540044.1:c.2926G>A, XM_011540045.1:c.3061G>A, XM_011540046.1:c.2521G>A, XM_011540047.1:c.1879G>A, XM_011540048.1:c.3061G>A, XM_011540049.1:c.3061G>A, XM_011540050.1:c.3061G>A, XM_011540051.1:c.3061G>A, XM_011540053.1:c.3061G>A, XM_011540054.1:c.3001G>A, XR_945796.1:n.3304G>A, XR_946052.1:n.83-448C>T, ENST00000224721.10:c.2881G>A, ENST00000299366.11:c.2866G>A, ENST00000398809.8:c.2866G>A, ENST00000442677.3:n.1641G>A, ENST00000466757.7:n.2297G>A, ENST00000616684.4:c.2866G>A, ENST00000622827.4:c.2866G>A, NC_000010.11:g.71705043G>A, CM000672.2:g.71705043G>A, NC_000010.10:g.73464800G>A, CM000672.1:g.73464800G>A, NC_000010.9:g.73134806G>A, NG_008835.1:g.313097G>A, NM_022124.5(CDH23):c.2866G>A (p.Glu956Lys) CDH23 sensorineural hearing loss disorder MONDO:0020678 Autosomal recessive inheritance Likely Pathogenic PP3 [MET], PM2-Supporting [MET], BP4 [Unmet], PM3-Strong [MET] The allele frequency of the c.2866G>A (p.Glu956Lys) variant in the CDH23 gene is 0.025% (6/23706) of African chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been reported in five probands with hearing loss without evidence of retinal disease (PMID 25963016, 22899989). Four of these individuals also harbored the p.Pro240Leu pathogenic variant in CDH23; however, only three were confirmed in trans (PM3_Strong, PMID 25963016, 22899989). The fifth individual also harbored the p.Asp645Gly variant in CDH23, but phasing was not performed (PMID 25963016). The REVEL computational prediction analysis tool produced a score of 0.616, which was just below the threshold to automatically apply PP3, but the Expert Panel decided to apply PP3 based upon manual review of alignments to examine homology. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_Strong, PM2_Supporting, PP3. 26763877, 25963016, 22899989 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA5544361/MONDO:0020678/005 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 7 140487375 448924 T C NM_004004.5(GJB2):c.677T>G (p.Val226Gly) 447450 CA6904209 NM_004004.5:c.677T>G, XM_011535049.1:c.677T>G, XM_011535049.2:c.677T>G, NM_004004.6:c.677T>G, ENST00000382844.1:c.677T>G, ENST00000382848.4:c.677T>G, NC_000013.11:g.20188905A>C, CM000675.2:g.20188905A>C, NC_000013.10:g.20763044A>C, CM000675.1:g.20763044A>C, NC_000013.9:g.19661044A>C, NG_008358.1:g.9071T>G, NM_004004.5(GJB2):c.677T>G (p.Val226Gly) GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], PP3 [Unmet], PP4 [Unmet], PP1 [Unmet], BS2 [Unmet], BA1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The c.677T>G (p.Val226Gly) variant has been identified in the heterozygous state in one individual with sensorineural hearing loss and one individual with breast or ovarian cancer in the literature (PS4 not met; 17666888 27153395). The allele frequency of the p.Val226Gly variant in the GJB2 gene is 0.003% (1/343458) of Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). In summary, this variant meets criteria to be classified as a variant of uncertain clinical significance for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2. 25388846, 25388846, 17666888, 27153395 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-14 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6904209/MONDO:0019497/005 0.0059 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 11 533618 448926 A C NM_004333.5(BRAF):c.1150A>G (p.Arg384Gly) 448924 CA4516796 NM_004333.5:c.1150A>G, NM_004333.4:c.1150A>G, LRG_299t1:c.1150A>G, XM_005250045.1:c.1150A>G, XM_005250046.1:c.1150A>G, XM_011516529.1:c.1150A>G, XM_011516530.1:c.1150A>G, XR_242190.1:n.1158A>G, XR_927520.1:n.1158A>G, XR_927521.1:n.1158A>G, XR_927522.1:n.1158A>G, XR_927523.1:n.1158A>G, NM_001354609.1:c.1150A>G, NR_148928.1:n.1455A>G, XM_017012558.1:c.1150A>G, XM_017012559.1:c.1150A>G, XR_001744857.1:n.1158A>G, XR_001744858.1:n.1158A>G, ENST00000288602.10:c.1150A>G, ENST00000497784.1:n.1185A>G, NC_000007.14:g.140787575T>C, CM000669.2:g.140787575T>C, NC_000007.13:g.140487375T>C, CM000669.1:g.140487375T>C, NC_000007.12:g.140133844T>C, NG_007873.3:g.142190A>G, LRG_299:g.142190A>G, NM_004333.5(BRAF):c.1150A>G (p.Arg384Gly) BRAF RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.1150A>G (p.Arg384Gly) variant in the BRAF gene is 0.116% (16/8646) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA4516796/MONDO:0021060/004 0.025 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 3 12626660 448927 C T NM_005343.3(HRAS):c.291-6T>G 448926 CA5779338 NM_005343.3:c.291-6T>G, NC_000011.10:g.533618A>C, CM000673.2:g.533618A>C, NC_000011.9:g.533618A>C, CM000673.1:g.533618A>C, NC_000011.8:g.523618A>C, NG_007666.1:g.6933T>G, NM_001130442.1:c.291-6T>G, NM_005343.2:c.291-6T>G, NM_176795.3:c.291-6T>G, XM_011519875.1:c.-424-4980A>C, XM_011519877.1:c.-162+5281A>C, XR_242795.1:n.490-6T>G, NM_001130442.2:c.291-6T>G, NM_001318054.1:c.-29-6T>G, NM_176795.4:c.291-6T>G, XM_011519875.2:c.-424-4980A>C, XM_011519877.2:c.-162+5281A>C, XM_017017167.1:c.-499-4905A>C, XM_017017168.1:c.-499-4905A>C, NM_005343.4:c.291-6T>G, ENST00000311189.7:c.291-6T>G, ENST00000397594.5:c.291-6T>G, ENST00000397596.6:c.291-6T>G, ENST00000417302.5:c.291-6T>G, ENST00000451590.5:c.291-6T>G, ENST00000479482.1:n.212-6T>G, ENST00000493230.5:c.291-6T>G, NM_005343.3(HRAS):c.291-6T>G LRRC56 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.291-6T>G variant in the HRAS gene is 0.051% (14/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA5779338/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 3 12641734 448928 T C NM_002880.3(RAF1):c.1629G>A (p.Thr543=) 448927 CA2259460 NM_002880.3:c.1629G>A, LRG_413t1:c.1629G>A, XM_005265355.1:c.1629G>A, XM_005265357.1:c.1530G>A, XM_005265358.3:c.1386G>A, XM_005265359.3:c.1287G>A, XM_011533974.1:c.1629G>A, XM_011533975.1:c.1386G>A, NM_001354689.1:c.1689G>A, NM_001354690.1:c.1629G>A, NM_001354691.1:c.1386G>A, NM_001354692.1:c.1386G>A, NM_001354693.1:c.1530G>A, NM_001354694.1:c.1446G>A, NM_001354695.1:c.1287G>A, NR_148940.1:n.2157G>A, NR_148941.1:n.2103G>A, NR_148942.1:n.2042G>A, XM_011533974.3:c.1629G>A, XM_017006966.1:c.1530G>A, ENST00000251849.8:c.1629G>A, ENST00000423275.5:c.*1306G>A, ENST00000432427.2:n.1266G>A, ENST00000442415.6:c.1689G>A, ENST00000471449.1:n.318G>A, NC_000003.12:g.12585161C>T, CM000665.2:g.12585161C>T, NC_000003.11:g.12626660C>T, CM000665.1:g.12626660C>T, NC_000003.10:g.12601660C>T, NG_007467.1:g.84019G>A, LRG_413:g.84019G>A, NM_002880.3(RAF1):c.1629G>A (p.Thr543=) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.438+8A>T variant in the MAP2K1 gene is 0.075% (19/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2018-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA2259460/MONDO:0021060/004 0.0028 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 3 12660097 448930 C T NM_002880.3(RAF1):c.907A>G (p.Thr303Ala) 448928 CA2259632 NM_002880.3:c.907A>G, LRG_413t1:c.907A>G, XM_005265355.1:c.907A>G, XM_005265357.1:c.808A>G, XM_005265358.3:c.664A>G, XM_005265359.3:c.565A>G, XM_005265360.1:c.907A>G, XM_011533974.1:c.907A>G, XM_011533975.1:c.664A>G, NM_001354689.1:c.967A>G, NM_001354690.1:c.907A>G, NM_001354691.1:c.664A>G, NM_001354692.1:c.664A>G, NM_001354693.1:c.808A>G, NM_001354694.1:c.724A>G, NM_001354695.1:c.565A>G, NR_148940.1:n.1322A>G, NR_148941.1:n.1322A>G, NR_148942.1:n.1322A>G, XM_011533974.3:c.907A>G, XM_017006966.1:c.808A>G, XR_001740227.1:n.1139A>G, ENST00000251849.8:c.907A>G, ENST00000423275.5:c.*584A>G, ENST00000432427.2:n.544A>G, ENST00000442415.6:c.967A>G, ENST00000465826.5:n.151A>G, ENST00000491290.1:n.536A>G, NC_000003.12:g.12600235T>C, CM000665.2:g.12600235T>C, NC_000003.11:g.12641734T>C, CM000665.1:g.12641734T>C, NC_000003.10:g.12616734T>C, NG_007467.1:g.68945A>G, LRG_413:g.68945A>G, NM_002880.3(RAF1):c.907A>G (p.Thr303Ala) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.907A>G (p.Thr303Ala) variant in the RAF1 gene is 0.0284% (7/11568) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA2259632/MONDO:0021060/004 0.0014 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 112724479 448931 G A NM_002880.3(RAF1):c.124G>A (p.Ala42Thr) 448930 CA2259833 NM_002880.3:c.124G>A, NC_000003.12:g.12618598C>T, CM000665.2:g.12618598C>T, NC_000003.11:g.12660097C>T, CM000665.1:g.12660097C>T, NC_000003.10:g.12635097C>T, NG_007467.1:g.50582G>A, LRG_413:g.50582G>A, LRG_413t1:c.124G>A, XM_005265355.1:c.124G>A, XM_005265357.1:c.124G>A, XM_005265358.3:c.-7G>A, XM_005265359.3:c.-7G>A, XM_005265360.1:c.124G>A, XM_011533974.1:c.124G>A, XM_011533975.1:c.-7G>A, NM_001354689.1:c.124G>A, NM_001354690.1:c.124G>A, NM_001354691.1:c.-7G>A, NM_001354692.1:c.-7G>A, NM_001354693.1:c.124G>A, NM_001354694.1:c.-7G>A, NM_001354695.1:c.-7G>A, NR_148940.1:n.539G>A, NR_148941.1:n.539G>A, NR_148942.1:n.539G>A, XM_011533974.3:c.124G>A, XM_017006966.1:c.124G>A, XR_001740227.1:n.455G>A, ENST00000251849.8:c.124G>A, ENST00000416093.1:c.124G>A, ENST00000423275.5:c.124G>A, ENST00000442415.6:c.124G>A, NM_002880.3(RAF1):c.124G>A (p.Ala42Thr) RAF1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.124G>A (p.Ala42Thr) variant in the RAF1 gene is 0.026% (25/66738) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA2259833/MONDO:0021060/004 0.0028 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 10 112724493 448932 C T NM_007373.3(SHOC2):c.363G>A (p.Glu121=) 448931 CA5689580 NM_007373.3:c.363G>A, NC_000010.11:g.110964721G>A, CM000672.2:g.110964721G>A, NC_000010.10:g.112724479G>A, CM000672.1:g.112724479G>A, NC_000010.9:g.112714469G>A, NG_028922.1:g.50179G>A, LRG_753:g.50179G>A, NM_001269039.1:c.363G>A, LRG_753t1:c.363G>A, XM_011540216.1:c.-380-20907G>A, NM_001269039.2:c.363G>A, NM_001324336.1:c.363G>A, NM_001324337.1:c.363G>A, NR_136749.1:n.116-20907G>A, ENST00000265277.9:c.363G>A, ENST00000369452.8:c.363G>A, ENST00000489390.1:n.56-35694G>A, ENST00000489783.1:n.741G>A, NM_007373.3(SHOC2):c.363G>A (p.Glu121=) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.363G>A (p.Glu121=) variant in the SHOC2 gene is 0.0384% (8/10350) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA5689580/MONDO:0021060/004 0.025 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 112724729 448933 A G NM_007373.3(SHOC2):c.377C>T (p.Thr126Ile) 448932 CA5689584 NM_007373.3:c.377C>T, NC_000010.11:g.110964735C>T, CM000672.2:g.110964735C>T, NC_000010.10:g.112724493C>T, CM000672.1:g.112724493C>T, NC_000010.9:g.112714483C>T, NG_028922.1:g.50193C>T, LRG_753:g.50193C>T, NM_001269039.1:c.377C>T, LRG_753t1:c.377C>T, XM_011540216.1:c.-380-20893C>T, NM_001269039.2:c.377C>T, NM_001324336.1:c.377C>T, NM_001324337.1:c.377C>T, NR_136749.1:n.116-20893C>T, ENST00000265277.9:c.377C>T, ENST00000369452.8:c.377C>T, ENST00000489390.1:n.56-35680C>T, NM_007373.3(SHOC2):c.377C>T (p.Thr126Ile) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.377C>T (p.Thr126Ile) variant in the SHOC2 gene is 0.0384% (8/10346) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA5689584/MONDO:0021060/004 0.0122 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 10 112760217 448934 C T NM_007373.3(SHOC2):c.613A>G (p.Thr205Ala) 448933 CA5689601 NM_007373.3:c.613A>G, NC_000010.11:g.110964971A>G, CM000672.2:g.110964971A>G, NC_000010.10:g.112724729A>G, CM000672.1:g.112724729A>G, NC_000010.9:g.112714719A>G, NG_028922.1:g.50429A>G, LRG_753:g.50429A>G, NM_001269039.1:c.613A>G, LRG_753t1:c.613A>G, XM_011540216.1:c.-380-20657A>G, NM_001269039.2:c.613A>G, NM_001324336.1:c.613A>G, NM_001324337.1:c.613A>G, NR_136749.1:n.116-20657A>G, ENST00000265277.9:c.613A>G, ENST00000369452.8:c.613A>G, ENST00000451838.1:n.121A>G, ENST00000489390.1:n.56-35444A>G, NM_007373.3(SHOC2):c.613A>G (p.Thr205Ala) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.613A>G (p.Thr205Ala) variant in the SHOC2 gene is 0.0328% (10/16502) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA5689601/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 10 112760225 448935 A C NM_007373.3(SHOC2):c.886C>T (p.Leu296=) 448934 CA5689679 NM_007373.3:c.886C>T, NC_000010.11:g.111000459C>T, CM000672.2:g.111000459C>T, NC_000010.10:g.112760217C>T, CM000672.1:g.112760217C>T, NC_000010.9:g.112750207C>T, NG_028922.1:g.85917C>T, LRG_753:g.85917C>T, NM_001269039.1:c.748C>T, LRG_753t1:c.886C>T, XM_011540216.1:c.-198C>T, NM_001269039.2:c.748C>T, NM_001324336.1:c.886C>T, NM_001324337.1:c.886C>T, NR_136749.1:n.298C>T, ENST00000265277.9:c.748C>T, ENST00000369452.8:c.886C>T, ENST00000451838.1:n.256C>T, ENST00000489390.1:n.100C>T, NM_007373.3(SHOC2):c.886C>T (p.Leu296=) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.886C>T (p.Leu296=) variant in the SHOC2 gene is 0.08% (15/11572) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA5689679/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 2 39213309 448938 C T NM_007373.3(SHOC2):c.894A>C (p.Ala298=) 448935 CA5689680 NM_007373.3:c.894A>C, NC_000010.11:g.111000467A>C, CM000672.2:g.111000467A>C, NC_000010.10:g.112760225A>C, CM000672.1:g.112760225A>C, NC_000010.9:g.112750215A>C, NG_028922.1:g.85925A>C, LRG_753:g.85925A>C, NM_001269039.1:c.756A>C, LRG_753t1:c.894A>C, XM_011540216.1:c.-190A>C, NM_001269039.2:c.756A>C, NM_001324336.1:c.894A>C, NM_001324337.1:c.894A>C, NR_136749.1:n.306A>C, ENST00000265277.9:c.756A>C, ENST00000369452.8:c.894A>C, ENST00000451838.1:n.264A>C, ENST00000489390.1:n.108A>C, NM_007373.3(SHOC2):c.894A>C (p.Ala298=) SHOC2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.894A>C (p.Ala298=) variant in the SHOC2 gene is 0.054% (9/8648) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA5689680/MONDO:0021060/004 0.0028 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 2 39213415 448939 A C NM_005633.3(SOS1):c.3658G>A (p.Val1220Met) 448938 CA1624132 NM_005633.3:c.3658G>A, LRG_754t1:c.3658G>A, XM_005264515.3:c.3613G>A, XM_011533060.1:c.3751G>A, XM_011533061.1:c.3706G>A, XM_011533062.1:c.3637G>A, XM_011533063.1:c.3634G>A, XM_011533064.1:c.3487G>A, XM_011533065.1:c.3604-805G>A, XM_011533066.1:c.2593G>A, XM_005264515.4:c.3613G>A, XM_011533062.2:c.3637G>A, XM_011533064.2:c.3487G>A, ENST00000395038.6:c.3613G>A, ENST00000402219.6:c.3658G>A, ENST00000426016.5:c.3658G>A, ENST00000469581.1:n.401G>A, NC_000002.12:g.38986168C>T, CM000664.2:g.38986168C>T, NC_000002.11:g.39213309C>T, CM000664.1:g.39213309C>T, NC_000002.10:g.39066813C>T, NG_007530.1:g.139296G>A, LRG_754:g.139296G>A, NM_005633.3(SOS1):c.3658G>A (p.Val1220Met) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.3658G>A (p.Val1220Met) variant in the SOS1 gene is 0.0328% (10/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624132/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 2 39222280 448940 C G NM_005633.3(SOS1):c.3552T>G (p.Pro1184=) 448939 CA1624148 NM_005633.3:c.3552T>G, LRG_754t1:c.3552T>G, XM_005264515.3:c.3507T>G, XM_011533060.1:c.3645T>G, XM_011533061.1:c.3600T>G, XM_011533062.1:c.3531T>G, XM_011533063.1:c.3528T>G, XM_011533064.1:c.3381T>G, XM_011533065.1:c.3604-911T>G, XM_011533066.1:c.2487T>G, XM_005264515.4:c.3507T>G, XM_011533062.2:c.3531T>G, XM_011533064.2:c.3381T>G, ENST00000395038.6:c.3507T>G, ENST00000402219.6:c.3552T>G, ENST00000426016.5:c.3552T>G, ENST00000469581.1:n.295T>G, NC_000002.12:g.38986274A>C, CM000664.2:g.38986274A>C, NC_000002.11:g.39213415A>C, CM000664.1:g.39213415A>C, NC_000002.10:g.39066919A>C, NG_007530.1:g.139190T>G, LRG_754:g.139190T>G, NM_005633.3(SOS1):c.3552T>G (p.Pro1184=) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.3552T>G (p.Pro1184=) variant in the SOS1 gene is 0.126% (17/8594) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624148/MONDO:0021060/004 0.0028 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 2 39224072 448941 G A NM_005633.3(SOS1):c.3330G>C (p.Ser1110=) 448940 CA1624221 NM_005633.3:c.3330G>C, LRG_754t1:c.3330G>C, XM_005264515.3:c.3330G>C, XM_011533060.1:c.3423G>C, XM_011533061.1:c.3423G>C, XM_011533062.1:c.3309G>C, XM_011533063.1:c.3306G>C, XM_011533064.1:c.3159G>C, XM_011533065.1:c.3423G>C, XM_011533066.1:c.2265G>C, XM_005264515.4:c.3330G>C, XM_011533062.2:c.3309G>C, XM_011533064.2:c.3159G>C, ENST00000395038.6:c.3330G>C, ENST00000402219.6:c.3330G>C, ENST00000426016.5:c.3330G>C, NC_000002.12:g.38995139C>G, CM000664.2:g.38995139C>G, NC_000002.11:g.39222280C>G, CM000664.1:g.39222280C>G, NC_000002.10:g.39075784C>G, NG_007530.1:g.130325G>C, LRG_754:g.130325G>C, NM_005633.3(SOS1):c.3330G>C (p.Ser1110=) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.3330G>C (p.Ser1110=) variant in the SOS1 gene is 0.0382% (8/10406) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624221/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 2 39241061 448942 C G NM_005633.3(SOS1):c.3072C>T (p.Leu1024=) 448941 CA1624273 NM_005633.3:c.3072C>T, LRG_754t1:c.3072C>T, XM_005264515.3:c.3072C>T, XM_011533060.1:c.3165C>T, XM_011533061.1:c.3165C>T, XM_011533062.1:c.3051C>T, XM_011533063.1:c.3048C>T, XM_011533064.1:c.2901C>T, XM_011533065.1:c.3165C>T, XM_011533066.1:c.2007C>T, XM_005264515.4:c.3072C>T, XM_011533062.2:c.3051C>T, XM_011533064.2:c.2901C>T, ENST00000395038.6:c.3072C>T, ENST00000402219.6:c.3072C>T, ENST00000426016.5:c.3072C>T, NC_000002.12:g.38996931G>A, CM000664.2:g.38996931G>A, NC_000002.11:g.39224072G>A, CM000664.1:g.39224072G>A, NC_000002.10:g.39077576G>A, NG_007530.1:g.128533C>T, LRG_754:g.128533C>T, NM_005633.3(SOS1):c.3072C>T (p.Leu1024=) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.3072C>T (p.Leu1024=) variant in the SOS1 gene is 0.075% (19/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624273/MONDO:0021060/004 0.0122 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 2 39285865 448944 C T NM_005633.3(SOS1):c.2010G>C (p.Leu670Phe) 448942 CA1624490 NM_005633.3:c.2010G>C, LRG_754t1:c.2010G>C, XM_005264515.3:c.2010G>C, XM_011533060.1:c.2103G>C, XM_011533061.1:c.2103G>C, XM_011533062.1:c.1989G>C, XM_011533063.1:c.1986G>C, XM_011533064.1:c.1839G>C, XM_011533065.1:c.2103G>C, XM_011533066.1:c.945G>C, XM_005264515.4:c.2010G>C, XM_011533062.2:c.1989G>C, XM_011533064.2:c.1839G>C, ENST00000395038.6:c.2010G>C, ENST00000402219.6:c.2010G>C, ENST00000426016.5:c.2010G>C, NC_000002.12:g.39013920C>G, CM000664.2:g.39013920C>G, NC_000002.11:g.39241061C>G, CM000664.1:g.39241061C>G, NC_000002.10:g.39094565C>G, NG_007530.1:g.111544G>C, LRG_754:g.111544G>C, NM_005633.3(SOS1):c.2010G>C (p.Leu670Phe) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.2010G>C (p.Leu670Phe) variant in the SOS1 gene is 0.055% (9/8572) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624490/MONDO:0021060/004 0.0028 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 2 39285879 448945 T C NM_005633.3(SOS1):c.294G>A (p.Lys98=) 448944 CA1624823 NM_005633.3:c.294G>A, NC_000002.12:g.39058724C>T, CM000664.2:g.39058724C>T, NC_000002.11:g.39285865C>T, CM000664.1:g.39285865C>T, NC_000002.10:g.39139369C>T, NG_007530.1:g.66740G>A, LRG_754:g.66740G>A, LRG_754t1:c.294G>A, XM_005264515.3:c.294G>A, XM_011533060.1:c.387G>A, XM_011533061.1:c.387G>A, XM_011533062.1:c.273G>A, XM_011533063.1:c.270G>A, XM_011533064.1:c.123G>A, XM_011533065.1:c.387G>A, XM_005264515.4:c.294G>A, XM_011533062.2:c.273G>A, XM_011533064.2:c.123G>A, ENST00000395038.6:c.294G>A, ENST00000402219.6:c.294G>A, ENST00000426016.5:c.294G>A, ENST00000451331.1:c.123G>A, NM_005633.3(SOS1):c.294G>A (p.Lys98=) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.294G>A (p.Lys98=) variant in the SOS1 gene is 0.0284% (9/16504) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624823/MONDO:0021060/004 0.025 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 2 39285934 448946 T C NM_005633.3(SOS1):c.280A>G (p.Ile94Val) 448945 CA1624825 NM_005633.3:c.280A>G, LRG_754t1:c.280A>G, XM_005264515.3:c.280A>G, XM_011533060.1:c.373A>G, XM_011533061.1:c.373A>G, XM_011533062.1:c.259A>G, XM_011533063.1:c.256A>G, XM_011533064.1:c.109A>G, XM_011533065.1:c.373A>G, XM_005264515.4:c.280A>G, XM_011533062.2:c.259A>G, XM_011533064.2:c.109A>G, ENST00000395038.6:c.280A>G, ENST00000402219.6:c.280A>G, ENST00000426016.5:c.280A>G, ENST00000451331.1:c.109A>G, NC_000002.12:g.39058738T>C, CM000664.2:g.39058738T>C, NC_000002.11:g.39285879T>C, CM000664.1:g.39285879T>C, NC_000002.10:g.39139383T>C, NG_007530.1:g.66726A>G, LRG_754:g.66726A>G, NM_005633.3(SOS1):c.280A>G (p.Ile94Val) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.280A>G (p.Ile94Val) variant in the SOS1 gene is 0.0253% (6/10300) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624825/MONDO:0021060/004 0.0028 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 2 39294841 448947 A G NM_005633.3(SOS1):c.225A>G (p.Gln75=) 448946 CA1624827 NM_005633.3:c.225A>G, NC_000002.12:g.39058793T>C, CM000664.2:g.39058793T>C, NC_000002.11:g.39285934T>C, CM000664.1:g.39285934T>C, NC_000002.10:g.39139438T>C, NG_007530.1:g.66671A>G, LRG_754:g.66671A>G, LRG_754t1:c.225A>G, XM_005264515.3:c.225A>G, XM_011533060.1:c.318A>G, XM_011533061.1:c.318A>G, XM_011533062.1:c.204A>G, XM_011533063.1:c.201A>G, XM_011533064.1:c.54A>G, XM_011533065.1:c.318A>G, XM_005264515.4:c.225A>G, XM_011533062.2:c.204A>G, XM_011533064.2:c.54A>G, ENST00000395038.6:c.225A>G, ENST00000402219.6:c.225A>G, ENST00000426016.5:c.225A>G, ENST00000451331.1:c.54A>G, NM_005633.3(SOS1):c.225A>G (p.Gln75=) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.225A>G (p.Gln75=) variant in the SOS1 gene is 0.042% (12/16448) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624827/MONDO:0021060/004 0.0059 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 15 66782869 448949 T C NM_005633.3(SOS1):c.141T>C (p.Tyr47=) 448947 CA1624855 NM_005633.3:c.141T>C, NC_000002.12:g.39067700A>G, CM000664.2:g.39067700A>G, NC_000002.11:g.39294841A>G, CM000664.1:g.39294841A>G, NC_000002.10:g.39148345A>G, NG_007530.1:g.57764T>C, LRG_754:g.57764T>C, LRG_754t1:c.141T>C, XM_005264515.3:c.141T>C, XM_011533060.1:c.234T>C, XM_011533061.1:c.234T>C, XM_011533062.1:c.120T>C, XM_011533063.1:c.117T>C, XM_011533064.1:c.-31T>C, XM_011533065.1:c.234T>C, XM_005264515.4:c.141T>C, XM_011533062.2:c.120T>C, XM_011533064.2:c.-31T>C, ENST00000395038.6:c.141T>C, ENST00000402219.6:c.141T>C, ENST00000426016.5:c.141T>C, ENST00000451331.1:c.-31T>C, NM_005633.3(SOS1):c.141T>C (p.Tyr47=) SOS1 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.141T>C (p.Tyr47=) variant in the SOS1 gene is 0.116% (16/8654) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-04-18 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1624855/MONDO:0021060/004 0.0028 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 19 4099271 448950 C A NM_002755.3(MAP2K1):c.1098T>C (p.Ala366=) 448949 CA7624163 NM_002755.3:c.1098T>C, NC_000015.10:g.66490531T>C, CM000677.2:g.66490531T>C, NC_000015.9:g.66782869T>C, CM000677.1:g.66782869T>C, NC_000015.8:g.64569923T>C, NG_008305.1:g.108659T>C, LRG_725:g.108659T>C, NG_051234.1:g.12285A>G, LRG_725t1:c.1098T>C, NM_006049.2:c.*208A>G, XM_011521783.1:c.1032T>C, NM_006049.3:c.*208A>G, NR_138061.1:n.727A>G, XM_011521783.3:c.1032T>C, XM_017022411.2:c.1020T>C, XM_017022412.1:c.954T>C, XM_017022413.1:c.570T>C, ENST00000307102.9:c.1098T>C, ENST00000395589.6:c.*208A>G, ENST00000563480.6:c.*208A>G, ENST00000566326.1:c.570T>C, NM_002755.3(MAP2K1):c.1098T>C (p.Ala366=) MAP2K1 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.1098T>C (p.Ala366=) variant in the MAP2K1 gene is 0.0459% (8/8654) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA7624163/MONDO:0021060/004 0.0003 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 0, 0] 1 Uncertain Significance 19 4117495 448952 G A NM_030662.3(MAP2K2):c.847G>T (p.Val283Leu) 448950 CA9090817 NM_030662.3:c.847G>T, LRG_750t1:c.847G>T, XM_006722799.2:c.705+1746G>T, XM_011528133.1:c.277G>T, XM_017026989.1:c.847G>T, XM_017026990.1:c.705+1746G>T, ENST00000262948.9:c.847G>T, ENST00000394867.8:c.556G>T, ENST00000593364.5:n.794G>T, ENST00000595715.1:n.662G>T, ENST00000597263.5:n.169+1746G>T, ENST00000599021.1:n.29+1746G>T, ENST00000600584.5:n.1407G>T, ENST00000601786.5:n.1148G>T, NC_000019.10:g.4099273C>A, CM000681.2:g.4099273C>A, NC_000019.9:g.4099271C>A, CM000681.1:g.4099271C>A, NC_000019.8:g.4050271C>A, NG_007996.1:g.29856G>T, LRG_750:g.29856G>T, NM_030662.3(MAP2K2):c.847G>T (p.Val283Leu) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.847G>T (p.Val283Leu) variant in the MAP2K2 gene is 0.0448% (6/5824) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA9090817/MONDO:0021060/004 0.0003 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 19 4117579 448953 G A NM_030662.3(MAP2K2):c.225C>T (p.Ile75=) 448952 CA9091075 NM_030662.3:c.225C>T, LRG_750t1:c.225C>T, XM_006722799.2:c.225C>T, XM_017026989.1:c.225C>T, XM_017026990.1:c.225C>T, XM_017026991.1:c.225C>T, ENST00000262948.9:c.225C>T, ENST00000394867.8:c.-67C>T, ENST00000599345.1:n.422C>T, NC_000019.10:g.4117497G>A, CM000681.2:g.4117497G>A, NC_000019.9:g.4117495G>A, CM000681.1:g.4117495G>A, NC_000019.8:g.4068495G>A, NG_007996.1:g.11632C>T, LRG_750:g.11632C>T, NM_030662.3(MAP2K2):c.225C>T (p.Ile75=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.225C>T (p.Ile75=) variant in the MAP2K2 gene is 0.08% (20/16508) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA9091075/MONDO:0021060/004 0.0003 Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 19 4123828 448954 G A NM_030662.3(MAP2K2):c.141C>T (p.Asp47=) 448953 CA9091086 NM_030662.3:c.141C>T, NC_000019.10:g.4117581G>A, CM000681.2:g.4117581G>A, NC_000019.9:g.4117579G>A, CM000681.1:g.4117579G>A, NC_000019.8:g.4068579G>A, NG_007996.1:g.11548C>T, LRG_750:g.11548C>T, LRG_750t1:c.141C>T, XM_006722799.2:c.141C>T, XM_017026989.1:c.141C>T, XM_017026990.1:c.141C>T, XM_017026991.1:c.141C>T, ENST00000262948.9:c.141C>T, ENST00000394867.8:c.-151C>T, ENST00000599345.1:n.338C>T, NM_030662.3(MAP2K2):c.141C>T (p.Asp47=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Benign BA1 [MET] The filtering allele frequency of the c.141C>T (p.Asp47=) variant in the MAP2K2 gene is 0.054% (9/8646) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA9091086/MONDO:0021060/004 0.0028 Likely Benign Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance 10 89653795 449088 CATT C NM_030662.3(MAP2K2):c.45C>T (p.Asn15=) 448954 CA9091108 NM_030662.3:c.45C>T, LRG_750t1:c.45C>T, XM_006722799.2:c.45C>T, XM_017026989.1:c.45C>T, XM_017026990.1:c.45C>T, XM_017026991.1:c.45C>T, ENST00000262948.9:c.45C>T, ENST00000394867.8:c.-231-16C>T, ENST00000599345.1:n.242C>T, NC_000019.10:g.4123831G>A, CM000681.2:g.4123831G>A, NC_000019.9:g.4123828G>A, CM000681.1:g.4123828G>A, NC_000019.8:g.4074828G>A, NG_007996.1:g.5299C>T, LRG_750:g.5299C>T, NM_030662.3(MAP2K2):c.45C>T (p.Asn15=) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Benign BS1 [MET] The filtering allele frequency of the c.45C>T (p.Asn15=) variant in the MAP2K2 gene is 0.0295% (6/8856) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf 2017-05-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA9091108/MONDO:0021060/004 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 1, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68835692 463775 C T NM_000314.6(PTEN):c.97_99delATT (p.Ile33del) 449088 CA645559009 NM_000314.6:c.97_99delATT, NC_000010.11:g.87894042_87894044del, CM000672.2:g.87894042_87894044del, NC_000010.10:g.89653799_89653801del, CM000672.1:g.89653799_89653801del, NC_000010.9:g.89643779_89643781del, NG_007466.2:g.35604_35606del, LRG_311:g.35604_35606del, NM_000314.5:c.97_99del, NM_000314.6:c.97_99del, NM_001304717.2:c.616_618del, NM_001304718.1:c.-609_-607del, XM_006717926.2:c.97_99del, XM_011539981.1:c.97_99del, XM_011539982.1:c.68+13604_68+13606del, XR_945789.1:n.809_811del, XR_945790.1:n.809_811del, XR_945791.1:n.809_811del, NM_000314.7:c.97_99del, NM_001304717.5:c.616_618del, NM_001304718.2:c.-609_-607del, ENST00000371953.7:c.97_99del, ENST00000462694.1:n.99_101del, ENST00000610634.1:c.-6_-4del, NM_000314.6(PTEN):c.97_99delATT (p.Ile33del) PTEN PTEN hamartoma tumor syndrome MONDO:0017623 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [MET], PVS1 [Unmet], BS2 [Unmet], PP2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], PS4-Supporting [MET], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [MET], PS2 [Unmet], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet] PTEN c.97_99delATT (p.I33del) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor SCV000616838.1)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor SCV000616838.1) 10234502, 29706350 PTEN VCEP https://www.clinicalgenome.org/site/assets/files/10250/pten_acmg_specifications_summary_v1_0_2018.pdf false https://erepo.genome.network/evrepo/ui/classification/CA645559009/MONDO:0017623/003 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36259274 463988 T TCC NM_004360.4(CDH1):c.283C>T (p.Gln95Ter) 463775 CA8129823 NM_004360.4:c.283C>T, NM_004360.3:c.283C>T, LRG_301t1:c.283C>T, XM_011523488.1:c.-453C>T, XM_011523489.1:c.-453C>T, NM_001317184.1:c.283C>T, NM_001317185.1:c.-1333C>T, NM_001317186.1:c.-1537C>T, ENST00000261769.9:c.283C>T, ENST00000422392.6:c.283C>T, ENST00000561751.1:n.50C>T, ENST00000562836.5:n.354C>T, ENST00000564676.5:n.565C>T, ENST00000564745.1:n.278C>T, ENST00000566510.5:c.283C>T, ENST00000566612.5:c.283C>T, ENST00000611625.4:c.283C>T, ENST00000612417.4:c.283C>T, ENST00000621016.4:c.283C>T, NC_000016.10:g.68801789C>T, CM000678.2:g.68801789C>T, NC_000016.9:g.68835692C>T, CM000678.1:g.68835692C>T, NC_000016.8:g.67393193C>T, NG_008021.1:g.69498C>T, LRG_301:g.69498C>T, NM_004360.4(CDH1):c.283C>T (p.Gln95Ter) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [MET], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP1 [Unmet], PP3 [Unmet], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS1 [Unmet], PS2 [Unmet], PS4-Moderate [MET] The c.283C>T (p.Gln95*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). The variant is present in <1/100,000 alleles in the gnomAD cohort. (PM2; http://gnomad.broadinstitute.org). This variant has been reported in at least 2 families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17545690, internal laboratory contributor). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1, PM2, PS4_Moderate. 17545690 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA8129823/MONDO:0007648/007 0.9971 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36421179 463989 T C NM_001754.4(RUNX1):c.215_216dup (p.Ser73Glyfs) 463988 CA658656806 NM_001754.4:c.215_216dup, NM_001754.4:c.215_216dupGG, NM_001001890.2:c.134_135dup, NM_001122607.1:c.134_135dup, LRG_482t1:c.215_216dup, XM_005261068.3:c.179_180dup, XM_005261069.3:c.215_216dup, XM_011529766.1:c.215_216dup, XM_011529767.1:c.176_177dup, XM_011529768.1:c.176_177dup, XM_011529770.1:c.215_216dup, XR_937576.1:n.394_395dup, XM_005261069.4:c.215_216dup, XM_011529766.2:c.215_216dup, XM_011529767.2:c.176_177dup, XM_011529768.2:c.176_177dup, XM_011529770.2:c.215_216dup, XM_017028487.1:c.62_63dup, XR_937576.2:n.441_442dup, ENST00000300305.7:c.215_216dup, ENST00000344691.8:c.134_135dup, ENST00000358356.9:c.134_135dup, ENST00000399237.6:c.179_180dup, ENST00000399240.5:c.134_135dup, ENST00000437180.5:c.215_216dup, ENST00000455571.5:c.176_177dup, ENST00000482318.5:c.59-6266_59-6265dup, NC_000021.9:g.34886978_34886979dup, CM000683.2:g.34886978_34886979dup, NC_000021.8:g.36259275_36259276dup, CM000683.1:g.36259275_36259276dup, NC_000021.7:g.35181145_35181146dup, NG_011402.2:g.1102733_1102734dup, LRG_482:g.1102733_1102734dup, NM_001754.4(RUNX1):c.215_216dup (p.Ser73Glyfs) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [MET] The NM_001754.4:c.215_216dup (p.Ser73Glyfs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; SCV000638134.1). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2, PS4_Supporting. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA658656806/MONDO:0011071/008 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 21 36252971 463994 T C NM_001754.4(RUNX1):c.18A>G (p.Ile6Met) 463989 CA10014733 NM_001754.4:c.18A>G, NC_000021.9:g.35048882T>C, CM000683.2:g.35048882T>C, NC_000021.8:g.36421179T>C, CM000683.1:g.36421179T>C, NC_000021.7:g.35343049T>C, NG_011402.2:g.940830A>G, LRG_482:g.940830A>G, LRG_482t1:c.18A>G, XM_005261069.3:c.18A>G, XM_011529766.1:c.18A>G, XM_011529767.1:c.18A>G, XM_011529768.1:c.18A>G, XM_011529770.1:c.18A>G, XR_937576.1:n.197A>G, XM_005261069.4:c.18A>G, XM_011529766.2:c.18A>G, XM_011529767.2:c.18A>G, XM_011529768.2:c.18A>G, XM_011529770.2:c.18A>G, XR_937576.2:n.244A>G, ENST00000300305.7:c.18A>G, ENST00000416754.1:c.18A>G, ENST00000437180.5:c.18A>G, ENST00000455571.5:c.18A>G, ENST00000475045.6:c.18A>G, ENST00000482318.5:c.18A>G, NM_001754.4(RUNX1):c.18A>G (p.Ile6Met) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Benign BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [MET], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] MAF for NM_001754.4:c.18A>G (p.Ile6Met) variant is 0.00025 (0.02%, 17/66732 Alleles) in the non-Finnish European subpopulation of ExAC database, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). Note: The variant is classified as likely benign based on BS1 alone with no contradictory evidence supporting pathogenicity. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014733/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36265254 464002 A T NM_001754.4(RUNX1):c.391A>G (p.Thr131Ala) 463994 CA410202714 NM_001754.4:c.391A>G, NM_001001890.2:c.310A>G, NM_001122607.1:c.310A>G, LRG_482t1:c.391A>G, XM_005261068.3:c.355A>G, XM_005261069.3:c.391A>G, XM_011529766.1:c.391A>G, XM_011529767.1:c.352A>G, XM_011529768.1:c.352A>G, XM_011529770.1:c.391A>G, XR_937576.1:n.570A>G, XM_005261069.4:c.391A>G, XM_011529766.2:c.391A>G, XM_011529767.2:c.352A>G, XM_011529768.2:c.352A>G, XM_011529770.2:c.391A>G, XM_017028487.1:c.238A>G, XR_937576.2:n.617A>G, ENST00000300305.7:c.391A>G, ENST00000344691.8:c.310A>G, ENST00000358356.9:c.310A>G, ENST00000399237.6:c.355A>G, ENST00000399240.5:c.310A>G, ENST00000437180.5:c.391A>G, ENST00000455571.5:c.352A>G, ENST00000482318.5:c.98A>G, NC_000021.9:g.34880674T>C, CM000683.2:g.34880674T>C, NC_000021.8:g.36252971T>C, CM000683.1:g.36252971T>C, NC_000021.7:g.35174841T>C, NG_011402.2:g.1109038A>G, LRG_482:g.1109038A>G, NM_001754.4(RUNX1):c.391A>G (p.Thr131Ala) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PM1-Supporting [MET], PS3 [Unmet], PS1 [Unmet], PS4 [Unmet], PM4 [Unmet], PM5 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [MET], PP1 [Unmet], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.391A>G (p.Thr131Ala) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score >0.75 (0.942) (PP3). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2, PP3, PM1_supporting. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410202714/MONDO:0011071/008 0.1877 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 21 36171741 464009 G A NM_001754.4(RUNX1):c.65T>A (p.Ile22Lys) 464002 CA10014634 NM_001754.4:c.65T>A, LRG_482t1:c.65T>A, XM_005261069.3:c.65T>A, XM_011529766.1:c.65T>A, XM_011529767.1:c.59-5861T>A, XM_011529768.1:c.59-5861T>A, XM_011529770.1:c.65T>A, XR_937576.1:n.244T>A, XM_005261069.4:c.65T>A, XM_011529766.2:c.65T>A, XM_011529767.2:c.59-5861T>A, XM_011529768.2:c.59-5861T>A, XM_011529770.2:c.65T>A, XR_937576.2:n.291T>A, ENST00000300305.7:c.65T>A, ENST00000416754.1:c.65T>A, ENST00000437180.5:c.65T>A, ENST00000455571.5:c.59-5861T>A, ENST00000475045.6:c.65T>A, ENST00000482318.5:c.59-12244T>A, NC_000021.9:g.34892957A>T, CM000683.2:g.34892957A>T, NC_000021.8:g.36265254A>T, CM000683.1:g.36265254A>T, NC_000021.7:g.35187124A>T, NG_011402.2:g.1096755T>A, LRG_482:g.1096755T>A, NM_001754.4(RUNX1):c.65T>A (p.Ile22Lys) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BA1 [MET], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.65T>A (p.Ile22Lys) variant has an MAF of 0.00201 (0.2%, 23/11436 alleles) in the Latino subpopulation of the ExAC cohort which is ≥ 0.0015 (0.15%) (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014634/MONDO:0011071/008 0.0122 Likely Benign Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 1, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 112888151 477669 T C NM_001754.4(RUNX1):c.824C>T (p.Pro275Leu) 464009 CA10014287 NM_001754.4:c.824C>T, NC_000021.9:g.34799444G>A, CM000683.2:g.34799444G>A, NC_000021.8:g.36171741G>A, CM000683.1:g.36171741G>A, NC_000021.7:g.35093611G>A, NG_011402.2:g.1190268C>T, LRG_482:g.1190268C>T, NM_001001890.2:c.743C>T, LRG_482t1:c.824C>T, XM_005261068.3:c.788C>T, XM_005261069.3:c.632C>T, XM_011529766.1:c.824C>T, XM_011529767.1:c.785C>T, XM_011529768.1:c.593C>T, XR_937576.1:n.1003C>T, XM_005261069.4:c.632C>T, XM_011529766.2:c.824C>T, XM_011529767.2:c.785C>T, XM_011529768.2:c.593C>T, XM_017028487.1:c.671C>T, XR_937576.2:n.1050C>T, ENST00000300305.7:c.824C>T, ENST00000344691.8:c.743C>T, ENST00000399240.5:c.551C>T, ENST00000437180.5:c.824C>T, ENST00000482318.5:c.*414C>T, NM_001754.4(RUNX1):c.824C>T (p.Pro275Leu) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Benign BA1 [MET], BP4 [MET], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], PP3 [Unmet], PP1 [Unmet], PVS1 [Unmet], PM2 [Unmet], PM6 [Unmet] The NM_001754.4:c.824C>T (p.Pro275Leu) variant has an MAF of 0.00225 (0.2%, 26/11566 alleles) in the Latino subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This missense variant has a REVEL score <0.15 (0.146) and SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA10014287/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68842699 479488 G T NM_002834.4(PTPN11):c.167T>C (p.Ile56Thr) 477669 CA243707917 NM_002834.4:c.167T>C, NM_002834.3:c.167T>C, LRG_614t1:c.167T>C, NM_080601.1:c.167T>C, XM_006719526.1:c.167T>C, XM_006719527.1:c.167T>C, XM_011538613.1:c.164T>C, NM_001330437.1:c.167T>C, NM_080601.2:c.167T>C, XM_011538613.2:c.164T>C, XM_017019722.1:c.164T>C, ENST00000351677.6:c.167T>C, ENST00000392597.5:c.167T>C, ENST00000635625.1:n.167T>C, NC_000012.12:g.112450347T>C, CM000674.2:g.112450347T>C, NC_000012.11:g.112888151T>C, CM000674.1:g.112888151T>C, NC_000012.10:g.111372534T>C, NG_007459.1:g.36616T>C, LRG_614:g.36616T>C, NM_002834.4(PTPN11):c.167T>C (p.Ile56Thr) PTPN11 RASopathy MONDO:0021060 Autosomal dominant inheritance Likely Pathogenic PP2 [MET], PP3 [MET], PP1 [Unmet], BS2 [Unmet], PS4-Supporting [MET], PM5 [MET], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS2 [Unmet], PS3 [Unmet], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], BS3 [Unmet], PM2 [MET], PM6 [Unmet], BP1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], BA1 [Unmet] The c.167T>C (p.Ile56Thr) variant in PTPN11 has been identified in 2 related patients with clinical features of a RASopathy (PS4_Supporting, PP1; Invitae internal data; GTR Lab ID 500031; ClinVar SCV000659038.1). A different pathogenic missense variant (p.Ile56Val) has been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40485). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Ile56Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PP1, PM2, PM5, PP2, PP3. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA243707917/MONDO:0021060/004 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 16 68867259 479504 G T NM_004360.4(CDH1):c.635G>T (p.Gly212Val) 479488 CA396458057 NM_004360.4:c.635G>T, NM_004360.3:c.635G>T, LRG_301t1:c.635G>T, XM_011523488.1:c.-101G>T, XM_011523489.1:c.-101G>T, NM_001317184.1:c.635G>T, NM_001317185.1:c.-981G>T, NM_001317186.1:c.-1185G>T, ENST00000261769.9:c.635G>T, ENST00000422392.6:c.635G>T, ENST00000561751.1:n.402G>T, ENST00000562836.5:n.706G>T, ENST00000564676.5:n.917G>T, ENST00000566510.5:c.531+229G>T, ENST00000566612.5:c.635G>T, ENST00000567320.1:n.145G>T, ENST00000611625.4:c.635G>T, ENST00000612417.4:c.635G>T, ENST00000621016.4:c.635G>T, NC_000016.10:g.68808796G>T, CM000678.2:g.68808796G>T, NC_000016.9:g.68842699G>T, CM000678.1:g.68842699G>T, NC_000016.8:g.67400200G>T, NG_008021.1:g.76505G>T, LRG_301:g.76505G>T, NM_004360.4(CDH1):c.635G>T (p.Gly212Val) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Uncertain Significance BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PS4-Supporting [MET], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet] The c.635G>T (p.Gly212Val) variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000661629.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: PM2, PS4_Supporting. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA396458057/MONDO:0007648/007 0.9986 Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68846113 483264 GT G NM_004360.4(CDH1):c.2506G>T (p.Glu836Ter) 479504 CA396472215 NM_004360.4:c.2506G>T, NM_004360.3:c.2506G>T, LRG_301t1:c.2506G>T, XM_011523488.1:c.1771G>T, XM_011523489.1:c.1771G>T, NM_001317184.1:c.2323G>T, NM_001317185.1:c.958G>T, NM_001317186.1:c.541G>T, ENST00000261769.9:c.2506G>T, ENST00000422392.6:c.2323G>T, ENST00000562118.1:n.724G>T, ENST00000562836.5:n.2577G>T, ENST00000566510.5:c.*1172G>T, ENST00000566612.5:c.*746G>T, ENST00000611625.4:c.2569G>T, ENST00000612417.4:c.1854-835G>T, ENST00000621016.4:c.1866-847G>T, NC_000016.10:g.68833356G>T, CM000678.2:g.68833356G>T, NC_000016.9:g.68867259G>T, CM000678.1:g.68867259G>T, NC_000016.8:g.67424760G>T, NG_008021.1:g.101065G>T, LRG_301:g.101065G>T, NM_004360.4(CDH1):c.2506G>T (p.Glu836Ter) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PVS1-Strong [MET], PM4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS2 [MET], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet] The c.2506G>T (p.Glu836*) variant results in a premature stop codon that leads to a truncated protein. While it is located within the nonsense mediated decay resistance region,it is recognized as the most c-terminal pathogenic variant in CDH1 (PVS1_Strong, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). There is one known de novo observation with parental confirmation in a patient with diffuse gastric cancer and/or lobular breast cancer (PS2; PMID: 29798843). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Strong, PM2, PS2. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA396472215/MONDO:0007648/007 0.9971 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68835787 486824 GC G NM_004360.4(CDH1):c.1085delT (p.Val362Glyfs) 483264 CA658658486 NM_004360.4:c.1085delT, NC_000016.10:g.68812211del, CM000678.2:g.68812211del, NC_000016.9:g.68846114del, CM000678.1:g.68846114del, NC_000016.8:g.67403615del, NG_008021.1:g.79920del, LRG_301:g.79920del, NM_004360.3:c.1085del, LRG_301t1:c.1085del, XM_011523488.1:c.350del, XM_011523489.1:c.350del, NM_001317184.1:c.1085del, NM_001317185.1:c.-531del, NM_001317186.1:c.-735del, NM_004360.4:c.1085del, ENST00000261769.9:c.1085del, ENST00000422392.6:c.1085del, ENST00000561751.1:n.707del, ENST00000562836.5:n.1156del, ENST00000565810.1:n.129del, ENST00000566510.5:c.929del, ENST00000566612.5:c.1085del, ENST00000611625.4:c.1085del, ENST00000612417.4:c.1085del, ENST00000621016.4:c.1085del, NM_004360.4(CDH1):c.1085delT (p.Val362Glyfs) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BS4 [Unmet], BS1 [Unmet], BP7 [Unmet], BP5 [Unmet], PVS1 [MET], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP1 [Unmet], PP3 [Unmet], PS4-Supporting [MET], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet] The c.1085delT (p.Val362Glyfs*31) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). The variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000669065.1). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1, PM2, PS4_Supporting. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA658658486/MONDO:0007648/007 0.9971 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 16 68842599 496233 A G NM_004360.4(CDH1):c.382delC (p.His128Ilefs) 486824 CA496152715 NM_004360.4:c.382delC, NM_004360.3:c.382del, LRG_301t1:c.382del, XM_011523488.1:c.-354del, XM_011523489.1:c.-354del, NM_001317184.1:c.382del, NM_001317185.1:c.-1234del, NM_001317186.1:c.-1438del, NM_004360.4:c.382del, ENST00000261769.9:c.382del, ENST00000422392.6:c.382del, ENST00000561751.1:n.149del, ENST00000562836.5:n.453del, ENST00000564676.5:n.664del, ENST00000564745.1:n.377del, ENST00000566510.5:c.382del, ENST00000566612.5:c.382del, ENST00000611625.4:c.382del, ENST00000612417.4:c.382del, ENST00000621016.4:c.382del, NC_000016.10:g.68801888del, CM000678.2:g.68801888del, NC_000016.9:g.68835791del, CM000678.1:g.68835791del, NC_000016.8:g.67393292del, NG_008021.1:g.69597del, LRG_301:g.69597del, NM_004360.4(CDH1):c.382delC (p.His128Ilefs) CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Pathogenic BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [MET], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PS4-Supporting [MET], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet] The c.382delC (p.His128Ilefs*87) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). The variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 15235021). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1, PM2, PS4_Supporting. 19269290 CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-21 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA496152715/MONDO:0007648/007 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 1 41285135 505302 G C NM_004360.3:c.535A>G 496233 CA396457842 NM_004360.3:c.535A>G, LRG_301t1:c.535A>G, XM_011523488.1:c.-201A>G, XM_011523489.1:c.-201A>G, NM_001317184.1:c.535A>G, NM_001317185.1:c.-1081A>G, NM_001317186.1:c.-1285A>G, NM_004360.4:c.535A>G, ENST00000261769.9:c.535A>G, ENST00000422392.6:c.535A>G, ENST00000561751.1:n.302A>G, ENST00000562836.5:n.606A>G, ENST00000564676.5:n.817A>G, ENST00000564745.1:n.530A>G, ENST00000566510.5:c.531+129A>G, ENST00000566612.5:c.535A>G, ENST00000567320.1:n.45A>G, ENST00000611625.4:c.535A>G, ENST00000612417.4:c.535A>G, ENST00000621016.4:c.535A>G, NC_000016.10:g.68808696A>G, CM000678.2:g.68808696A>G, NC_000016.9:g.68842599A>G, CM000678.1:g.68842599A>G, NC_000016.8:g.67400100A>G, NG_008021.1:g.76405A>G, LRG_301:g.76405A>G CDH1 hereditary diffuse gastric cancer MONDO:0007648 Autosomal dominant inheritance Uncertain Significance BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet], PVS1 [Unmet], PM2 [MET], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP1 [MET], PS4-Supporting [MET], PM4 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS2 [Unmet] The c.535A>G (p.Lys179Glu) variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 3 or 4 meioses observed (PP1; internal laboratory contributor). This variant has also been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; internal laboratory contributor). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: PM2, PP1, PS4_Supporting. CDH1 VCEP https://www.clinicalgenome.org/site/assets/files/8816/clingen_cdh1_acmg_specifications_v1.pdf 2018-11-22 2018-12-07 false https://erepo.genome.network/evrepo/ui/classification/CA396457842/MONDO:0007648/007 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 1 215932085 506273 G T NM_004700.3(KCNQ4):c.825G>C (p.Trp275Cys) 505302 CA21112664 NM_004700.3:c.825G>C, NC_000001.11:g.40819463G>C, CM000663.2:g.40819463G>C, NC_000001.10:g.41285135G>C, CM000663.1:g.41285135G>C, NC_000001.9:g.41057722G>C, NG_008139.1:g.40452G>C, NG_008139.2:g.40452G>C, NM_172163.2:c.825G>C, XM_011542417.1:c.825G>C, XM_011542418.1:c.825G>C, XM_011542419.1:c.825G>C, XM_011542420.1:c.825G>C, XR_946798.1:n.831G>C, XR_946799.1:n.831G>C, XR_946800.1:n.831G>C, XM_017002792.1:c.-193G>C, NM_004700.4:c.825G>C, ENST00000347132.9:c.825G>C, ENST00000443478.3:n.511G>C, ENST00000506017.1:n.144G>C, ENST00000509682.6:n.825G>C, NM_004700.3(KCNQ4):c.825G>C (p.Trp275Cys) KCNQ4 nonsyndromic genetic deafness MONDO:0019497 Autosomal dominant inheritance Likely Pathogenic PM2 [MET], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP1 [Unmet], PP4 [Unmet], PP3 [MET], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], PS4 [Unmet], PS3 [Unmet], PS2 [Unmet], PS1 [Unmet], PM5 [MET], PM3 [Unmet], PM4 [Unmet], PM1 [MET], BS1 [Unmet], BS4 [Unmet], BP5 [Unmet], BP7 [Unmet] The c.825G>C (p.Trp275Cys) variant was found in one patient with hearing loss (PS4 not met; Partners LMM ClinVar SCV000712456.1). The p.Trp275Cys variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). A different pathogenic missense variant (p.Trp275Arg) and a likely pathogenic missense variant (p.Trp275Ser) have been previously identified at this codon of KCNQ4 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 6242, PMID: 25116015, 20301388; ClinVar Variation ID 372951). Furthermore, the variant is in a location that has been defined by the ClinGen Hearing Loss Expert Panel to be a mutational hotspot or domain of KCNQ4 (PM1; PMID: 23717403 https://www.uniprot.org/uniprot/P56696). Computational prediction tools and conservation analysis suggest that the p.Trp275Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant non-syndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: (PM2, PM5, PM1, PP3). Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA21112664/MONDO:0019497/005 0.9971 Pathogenic Likely pathogenic InterVar: Likely pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 11 76883813 517357 G A NM_206933.2(USH2A):c.11241C>A (p.Tyr3747Ter) 506273 CA1393780 NM_206933.2:c.11241C>A, NC_000001.11:g.215758743G>T, CM000663.2:g.215758743G>T, NC_000001.10:g.215932085G>T, CM000663.1:g.215932085G>T, NC_000001.9:g.213998708G>T, NG_009497.1:g.669654C>A, NM_206933.3:c.11241C>A, ENST00000307340.7:c.11241C>A, NM_206933.2(USH2A):c.11241C>A (p.Tyr3747Ter) USH2A Usher syndrome MONDO:0019501 Autosomal recessive inheritance Pathogenic PM6 [Unmet], PVS1 [MET], BS2 [Unmet], PP3 [Unmet], PP1 [Unmet], PP4 [Unmet], PM2-Supporting [MET], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3-Supporting [MET], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The p.Tyr3747X variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 58/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). The allele frequency of the p.Tyr3747X variant in the Ush2A gene is 0.017% (4/24020) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss ( PM2_Supporting). This variant has been detected in 1 patient with hearing loss in trans with a suspected pathogenic variant (PM3_Supporting, Partners LMM internal data SCV000713838.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied: PVS1, PM2_Supporting, PM3_Supporting. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-17 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA1393780/MONDO:0019501/005 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 21 36231821 532659 G C NM_000260.3(MYO7A):c.1817G>A (p.Arg606His) 517357 CA6197622 NM_000260.3:c.1817G>A, NM_001127179.2:c.1817G>A, NM_001127180.1:c.1817G>A, XM_005274012.2:c.1817G>A, XM_006718558.2:c.1817G>A, XM_006718559.2:c.1817G>A, XM_006718560.2:c.1817G>A, XM_006718561.2:c.1817G>A, XM_011545044.1:c.1817G>A, XM_011545045.1:c.1817G>A, XM_011545046.1:c.1784G>A, XM_011545047.1:c.1817G>A, XM_011545048.1:c.1817G>A, XM_011545049.1:c.1586G>A, XM_011545050.1:c.1559G>A, XM_011545051.1:c.1817G>A, XM_011545052.1:c.1817G>A, XR_949938.1:n.2137G>A, XR_949941.1:n.2137G>A, XR_949942.1:n.2139G>A, XR_949943.1:n.2139G>A, XM_011545044.2:c.1817G>A, XM_011545046.2:c.1907G>A, XM_011545050.2:c.1559G>A, XM_017017778.1:c.1907G>A, XM_017017779.1:c.1907G>A, XM_017017780.1:c.1907G>A, XM_017017781.1:c.1907G>A, XM_017017782.1:c.1907G>A, XM_017017783.1:c.1907G>A, XM_017017784.1:c.1907G>A, XM_017017785.1:c.1676G>A, XM_017017786.1:c.1907G>A, XM_017017787.1:c.1907G>A, XM_017017788.1:c.1907G>A, XR_001747885.1:n.1922G>A, XR_001747886.1:n.1922G>A, XR_001747887.1:n.1922G>A, XR_001747888.1:n.1922G>A, XR_001747889.1:n.1922G>A, NM_000260.4:c.1817G>A, ENST00000409619.6:c.1784G>A, ENST00000409709.7:c.1817G>A, ENST00000409893.5:c.1817G>A, ENST00000458637.6:c.1817G>A, ENST00000620575.4:c.1817G>A, NC_000011.10:g.77172767G>A, CM000673.2:g.77172767G>A, NC_000011.9:g.76883813G>A, CM000673.1:g.76883813G>A, NC_000011.8:g.76561461G>A, NG_009086.1:g.49504G>A, NM_000260.3(MYO7A):c.1817G>A (p.Arg606His) MYO7A nonsyndromic genetic deafness MONDO:0019497 Uncertain Significance PM6 [Unmet], PVS1 [Unmet], PP3 [MET], PP1 [Unmet], PP4 [MET], BS2 [Unmet], PM2-Supporting [MET], BA1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [MET], BP7 [Unmet], BP5 [Unmet], BS1 [Unmet], BS4 [Unmet] The allele frequency of the p.Arg505His variant in MYO7A is 0.035% (8/23150) South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). This variant has been detected in 1 patient with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3; Partners LMM internal data SCV000731600.1). Computational prediction tools and conservation analysis suggest that the p.Arg606His variant may impact the protein (PP3). One patient with a variant in this gene displayed features of sensorineural hearing loss and delayed walking (PP4; Partners LMM internal data SCV000731600.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_P, PM3, PP3, PP4. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-28 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6197622/MONDO:0019497/005 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 21 36164715 532662 C G NM_001754.4(RUNX1):c.563C>G (p.Thr188Ser) 532659 CA410208042 NM_001754.4:c.563C>G, NM_001001890.2:c.482C>G, NM_001122607.1:c.482C>G, LRG_482t1:c.563C>G, XM_005261068.3:c.527C>G, XM_005261069.3:c.563C>G, XM_011529766.1:c.563C>G, XM_011529767.1:c.524C>G, XM_011529768.1:c.524C>G, XM_011529770.1:c.563C>G, XR_937576.1:n.742C>G, XM_005261069.4:c.563C>G, XM_011529766.2:c.563C>G, XM_011529767.2:c.524C>G, XM_011529768.2:c.524C>G, XM_011529770.2:c.563C>G, XM_017028487.1:c.410C>G, XR_937576.2:n.789C>G, ENST00000300305.7:c.563C>G, ENST00000344691.8:c.482C>G, ENST00000358356.9:c.482C>G, ENST00000399237.6:c.527C>G, ENST00000399240.5:c.482C>G, ENST00000437180.5:c.563C>G, ENST00000467577.1:n.55C>G, ENST00000482318.5:c.*153C>G, NC_000021.9:g.34859524G>C, CM000683.2:g.34859524G>C, NC_000021.8:g.36231821G>C, CM000683.1:g.36231821G>C, NC_000021.7:g.35153691G>C, NG_011402.2:g.1130188C>G, LRG_482:g.1130188C>G, NM_001754.4(RUNX1):c.563C>G (p.Thr188Ser) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PM1-Supporting [MET], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM5 [Unmet], PM4 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [MET], PP1 [Unmet], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.563C>G (p.Thr188Ser) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score >0.75 (0.922) (PP3). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2, PP3, PM1_supporting. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410208042/MONDO:0011071/008 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 21 36164461 532664 G GGC NM_001754.4(RUNX1):c.1160G>C (p.Gly387Ala) 532662 CA410147917 NM_001754.4:c.1160G>C, NC_000021.9:g.34792418C>G, CM000683.2:g.34792418C>G, NC_000021.8:g.36164715C>G, CM000683.1:g.36164715C>G, NC_000021.7:g.35086585C>G, NG_011402.2:g.1197294G>C, LRG_482:g.1197294G>C, NM_001001890.2:c.1079G>C, LRG_482t1:c.1160G>C, XM_005261068.3:c.1124G>C, XM_005261069.3:c.968G>C, XM_011529766.1:c.1160G>C, XM_011529767.1:c.1121G>C, XM_011529768.1:c.929G>C, XM_005261069.4:c.968G>C, XM_011529766.2:c.1160G>C, XM_011529767.2:c.1121G>C, XM_011529768.2:c.929G>C, XM_017028487.1:c.1007G>C, ENST00000300305.7:c.1160G>C, ENST00000344691.8:c.1079G>C, ENST00000399240.5:c.887G>C, ENST00000437180.5:c.1160G>C, ENST00000482318.5:c.*750G>C, NM_001754.4(RUNX1):c.1160G>C (p.Gly387Ala) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BP2 [Unmet], BP4 [MET], BA1 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PS1 [Unmet], PS3 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet], BS3 [Unmet], PP1 [Unmet], PP3 [Unmet], PS4-Supporting [MET], PM2 [Unmet], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.1160G>C (p.Gly387Ala) variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27210295). This missense variant has a REVEL score <0.15 (0.141) and SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). The gnomAD Allele Frequency of this variant is 0.00001. In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_ supporting, BP4. 27210295 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410147917/MONDO:0011071/008 0.9941 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36259160 532671 T C NM_001754.4(RUNX1):c.1412_1413dup (p.Leu472Alafs) 532664 CA658799413 NM_001754.4:c.1412_1413dupGC, NM_001754.4:c.1412_1413dup, NC_000021.9:g.34792170_34792171dup, CM000683.2:g.34792170_34792171dup, NC_000021.8:g.36164467_36164468dup, CM000683.1:g.36164467_36164468dup, NC_000021.7:g.35086337_35086338dup, NG_011402.2:g.1197546_1197547dup, LRG_482:g.1197546_1197547dup, NM_001001890.2:c.1331_1332dup, LRG_482t1:c.1412_1413dup, XM_005261068.3:c.1376_1377dup, XM_005261069.3:c.1220_1221dup, XM_011529766.1:c.1412_1413dup, XM_011529767.1:c.1373_1374dup, XM_011529768.1:c.1181_1182dup, XM_005261069.4:c.1220_1221dup, XM_011529766.2:c.1412_1413dup, XM_011529767.2:c.1373_1374dup, XM_011529768.2:c.1181_1182dup, XM_017028487.1:c.1259_1260dup, ENST00000300305.7:c.1412_1413dup, ENST00000344691.8:c.1331_1332dup, ENST00000399240.5:c.1139_1140dup, ENST00000437180.5:c.1412_1413dup, ENST00000482318.5:c.*1002_*1003dup, NM_001754.4(RUNX1):c.1412_1413dup (p.Leu472Alafs) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], PP1-Strong [MET], PVS1-Strong [MET], PP3 [Unmet], PS4-Supporting [MET], PS3-Moderate [MET], PM2 [MET], PM6 [Unmet] The NM_001754.4:c.1412_1413dup (p.Leu472Alafs) variant is a frameshift variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region (removes aa 472-480, including the VWRPY motif) is critical to protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 24353905). This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 24353905). There is evidence of abnormal protein expression of this variant allele as a functional consequence of incorrect protein products (PS3_Moderate; PMID: 24353905). PS3_Moderate is applied because the variant meets PVS1_Strong. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PP1_strong, PS3_moderate, PM2, PS4_supporting. 24353905, 24353905, 24353905, 24353905 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA658799413/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 19 4101030 543999 C T NM_001754.4(RUNX1):c.331A>G (p.Thr111Ala) 532671 CA410203415 NM_001754.4:c.331A>G, NM_001001890.2:c.250A>G, NM_001122607.1:c.250A>G, LRG_482t1:c.331A>G, XM_005261068.3:c.295A>G, XM_005261069.3:c.331A>G, XM_011529766.1:c.331A>G, XM_011529767.1:c.292A>G, XM_011529768.1:c.292A>G, XM_011529770.1:c.331A>G, XR_937576.1:n.510A>G, XM_005261069.4:c.331A>G, XM_011529766.2:c.331A>G, XM_011529767.2:c.292A>G, XM_011529768.2:c.292A>G, XM_011529770.2:c.331A>G, XM_017028487.1:c.178A>G, XR_937576.2:n.557A>G, ENST00000300305.7:c.331A>G, ENST00000344691.8:c.250A>G, ENST00000358356.9:c.250A>G, ENST00000399237.6:c.295A>G, ENST00000399240.5:c.250A>G, ENST00000437180.5:c.331A>G, ENST00000455571.5:c.292A>G, ENST00000482318.5:c.59-6150A>G, NC_000021.9:g.34886863T>C, CM000683.2:g.34886863T>C, NC_000021.8:g.36259160T>C, CM000683.1:g.36259160T>C, NC_000021.7:g.35181030T>C, NG_011402.2:g.1102849A>G, LRG_482:g.1102849A>G, NM_001754.4(RUNX1):c.331A>G (p.Thr111Ala) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS1 [Unmet], PS4 [Unmet], PM1-Supporting [MET], PM4 [Unmet], PM5 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [MET], PP1 [Unmet], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.331A>G (p.Thr111Ala) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score >0.75 (0.939) (PP3). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2, PP3, PM1_supporting. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410203415/MONDO:0011071/008 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36206833 545522 C A NM_030662.3(MAP2K2):c.692G>A (p.Arg231His) 543999 CA9090854 NM_030662.3:c.692G>A, LRG_750t1:c.692G>A, XM_006722799.2:c.692G>A, XM_011528133.1:c.122G>A, XM_017026989.1:c.692G>A, XM_017026990.1:c.692G>A, XM_017026991.1:c.692G>A, ENST00000262948.9:c.692G>A, ENST00000394867.8:c.401G>A, ENST00000593364.5:n.639G>A, ENST00000597008.5:n.293G>A, ENST00000597263.5:n.156G>A, ENST00000599021.1:n.16G>A, ENST00000601786.5:n.993G>A, ENST00000602167.5:n.412G>A, NC_000019.10:g.4101032C>T, CM000681.2:g.4101032C>T, NC_000019.9:g.4101030C>T, CM000681.1:g.4101030C>T, NC_000019.8:g.4052030C>T, NG_007996.1:g.28097G>A, LRG_750:g.28097G>A, NM_030662.3(MAP2K2):c.692G>A (p.Arg231His) MAP2K2 RASopathy MONDO:0021060 Autosomal dominant inheritance Uncertain Significance PP1 [Unmet], PP2 [MET], PP3 [MET], BS2 [Unmet], PM1 [Unmet], PM4 [Unmet], PM5 [Unmet], PS4 [Unmet], PS3 [Unmet], PS2 [Unmet], PS1 [Unmet], BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS3 [Unmet], BS4 [Unmet], PM2 [Unmet], PM6 [Unmet], BP1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], BA1 [Unmet] The c.692G>A (p.Arg231His) variant in MAP2K2 has been identified in a patient with clinical features consistent with cardiomyopathy (PS4 not met; Invitae internal data, GTR Lab ID 500031; ClinVar SCV000776886.1). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg231His variant may impact the protein (PP3). In summary, the clinical significance of the p.Arg231His variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3. RASopathy VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/pdyydcyt/acmg_variant_classification_rasopathy_.pdf false https://erepo.genome.network/evrepo/ui/classification/CA9090854/MONDO:0021060/004 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103234208 551555 G T NM_001001890.2(RUNX1):c.598G>T (p.Glu200Ter) 545522 CA410206910 NM_001001890.2:c.598G>T, NM_001122607.1:c.598G>T, NM_001754.4:c.679G>T, LRG_482t1:c.679G>T, XM_005261068.3:c.643G>T, XM_005261069.3:c.613+24938G>T, XM_011529766.1:c.679G>T, XM_011529767.1:c.640G>T, XM_011529768.1:c.574+24938G>T, XM_011529770.1:c.679G>T, XR_937576.1:n.858G>T, XM_005261069.4:c.613+24938G>T, XM_011529766.2:c.679G>T, XM_011529767.2:c.640G>T, XM_011529768.2:c.574+24938G>T, XM_011529770.2:c.679G>T, XM_017028487.1:c.526G>T, XR_937576.2:n.905G>T, ENST00000300305.7:c.679G>T, ENST00000344691.8:c.598G>T, ENST00000358356.9:c.598G>T, ENST00000399237.6:c.643G>T, ENST00000399240.5:c.532+24938G>T, ENST00000437180.5:c.679G>T, ENST00000469087.1:n.215G>T, ENST00000482318.5:c.*269G>T, NC_000021.9:g.34834536C>A, CM000683.2:g.34834536C>A, NC_000021.8:g.36206833C>A, CM000683.1:g.36206833C>A, NC_000021.7:g.35128703C>A, NG_011402.2:g.1155176G>T, LRG_482:g.1155176G>T, NM_001001890.2(RUNX1):c.598G>T (p.Glu200Ter) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Pathogenic BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS3 [Unmet], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [Unmet], PP1 [Unmet], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [MET] The NM_001001890.2:c.598G>T (p.Glu200Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 30990344). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2, PS4_Supporting. 30990344 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410206910/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 1 Uncertain Significance 12 103234275 552907 T C NM_000277.1:c.1285C>A 551555 CA6748701 NM_000277.1:c.1285C>A, XM_011538422.1:c.1228C>A, NM_000277.2:c.1285C>A, NM_001354304.1:c.1285C>A, NM_000277.3:c.1285C>A, ENST00000307000.7:c.1270C>A, ENST00000551114.2:n.947C>A, ENST00000553106.5:c.1285C>A, ENST00000635477.1:n.389C>A, ENST00000635528.1:n.800C>A, NC_000012.12:g.102840430G>T, CM000674.2:g.102840430G>T, NC_000012.11:g.103234208G>T, CM000674.1:g.103234208G>T, NC_000012.10:g.101758338G>T, NG_008690.1:g.82173C>A, NG_008690.2:g.122981C>A PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [Unmet] The c.1285C>A (p.Gln429Lys) variant in PAH is reported in a patient with mild PKU (Phe level 720). BH4 cofactor deficiency was excluded. It was detected with a known pathogenic variant, EX6-96A>G (VarID 590). (PMID: 26503515, 28982351) This variant has a low frequency in gnomAD and ExAC (MAF=0.00002), and absent in 1000G. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3. 26503515, 28982351, 28982351 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6748701/MONDO:0009861/006 0.6752 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103288698 555212 T C NM_000277.1:c.1218A>G 552907 CA6748708 NM_000277.1:c.1218A>G, NC_000012.12:g.102840497T>C, CM000674.2:g.102840497T>C, NC_000012.11:g.103234275T>C, CM000674.1:g.103234275T>C, NC_000012.10:g.101758405T>C, NG_008690.1:g.82106A>G, NG_008690.2:g.122914A>G, XM_011538422.1:c.1161A>G, NM_000277.2:c.1218A>G, NM_001354304.1:c.1218A>G, NM_000277.3:c.1218A>G, ENST00000307000.7:c.1203A>G, ENST00000551114.2:n.880A>G, ENST00000553106.5:c.1218A>G, ENST00000635477.1:n.322A>G, ENST00000635528.1:n.733A>G PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PM5 [MET], PM3 [MET], PP3 [Unmet], PP4 [MET] The c.1218A>G (p.Ile406Met) variant in PAH is reported in 2 individuals with non-PKU HPA. BH4 assessment was not stated. It was detected with a known pathogenic variant, p.Arg408Trp. (PMID: 23357515) This variant has a low allele frequency in gnomAD and ExAC (MAF=0.00003) and is absent in 1000G. Computational evidence is discordant. Another missense change at this amino acid is interpreted as likely pathogenic by the PAH VCEP (p.I406T). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PM5, PP4. 23357515, 23357515 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-09 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6748708/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103249097 555366 G A NM_000277.2(PAH):c.523C>T (p.Pro175Ser) 555366 CA16020810 NM_000277.2:c.523C>T, NM_000277.1:c.523C>T, XM_011538422.1:c.523C>T, NM_001354304.1:c.523C>T, XM_017019370.2:c.523C>T, NM_000277.3:c.523C>T, ENST00000307000.7:c.508C>T, ENST00000549111.5:n.619C>T, ENST00000551988.5:n.544C>T, ENST00000553106.5:c.523C>T, NC_000012.12:g.102855319G>A, CM000674.2:g.102855319G>A, NC_000012.11:g.103249097G>A, CM000674.1:g.103249097G>A, NC_000012.10:g.101773227G>A, NG_008690.1:g.67284C>T, NG_008690.2:g.108092C>T, NM_000277.2(PAH):c.523C>T (p.Pro175Ser) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PP4-Moderate [MET], PM3 [MET], PP3 [MET] The c.523C>T (p.Pro175Ser) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency excluded) in trans with pathogenic variant p.R413P (PP4_Moderate, PM3; PMID: 26322415). This variant is absent in population databases (PM2). Computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. 26322415, 26322415 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA16020810/MONDO:0009861/006 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763047 555720 G A NM_004004.5:c.674C>T 555720 CA387460667 NM_004004.5:c.674C>T, NC_000013.11:g.20188908G>A, CM000675.2:g.20188908G>A, NC_000013.10:g.20763047G>A, CM000675.1:g.20763047G>A, NC_000013.9:g.19661047G>A, NG_008358.1:g.9068C>T, XM_011535049.1:c.674C>T, XM_011535049.2:c.674C>T, NM_004004.6:c.674C>T, ENST00000382844.1:c.674C>T, ENST00000382848.4:c.674C>T GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [Unmet], PP4 [Unmet], PP1 [Unmet], BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], BP3 [Unmet], PS3 [Unmet], PS2 [Unmet], PS4 [Unmet], PS1 [Unmet], PM3 [MET], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] The p.Pro225Leu variant in GJB2 is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). This variant has been detected in 1 patient with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3; PMID:21112098). In summary, this variant meets criteria to be classified as a variant of uncertain clinical significance for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3. 21112098, 21112098 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-20 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA387460667/MONDO:0019497/005 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246635 556296 T C NM_000277.1:c.800A>G 556296 CA16020862 NM_000277.1:c.800A>G, NC_000012.12:g.102852857T>C, CM000674.2:g.102852857T>C, NC_000012.11:g.103246635T>C, CM000674.1:g.103246635T>C, NC_000012.10:g.101770765T>C, NG_008690.1:g.69746A>G, NG_008690.2:g.110554A>G, XM_011538422.1:c.800A>G, NM_000277.2:c.800A>G, NM_001354304.1:c.800A>G, NM_000277.3:c.800A>G, ENST00000307000.7:c.785A>G, ENST00000549247.6:n.559A>G, ENST00000553106.5:c.800A>G PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PP4-Moderate [MET], PM5 [Unmet], PM3 [MET], PP3 [MET], PS3 [MET] The c.800A>G (p.Gln267Arg) variant in PAH has been reported in 1 individual with Classic PKU (BH4 deficiency excluded) and was detected with G257V which is pathogenic per the ClinGen PAH VCEP (PP4_Moderate, PM3; PMID: 24401910). This variant is absent in population databases (PM2). This variant has 1.1% enzyme activity (PS3; PMID: 24401910). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PP3. 24401910, 24401910, 24401910 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-12-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA16020862/MONDO:0009861/006 0.8121 VUS Likely pathogenic InterVar: Likely pathogenic PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 1, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103306610 557124 C A NM_000277.2(PAH):c.127G>T (p.Glu43Ter) 557124 CA16020729 NM_000277.2:c.127G>T, NM_000277.1:c.127G>T, XM_011538422.1:c.127G>T, NM_001354304.1:c.127G>T, XM_017019370.2:c.127G>T, NM_000277.3:c.127G>T, ENST00000307000.7:c.112G>T, ENST00000546844.1:c.127G>T, ENST00000548677.2:n.214G>T, ENST00000548928.1:n.49G>T, ENST00000549111.5:n.223G>T, ENST00000550978.6:n.111G>T, ENST00000551337.5:c.127G>T, ENST00000551988.5:n.216G>T, ENST00000553106.5:c.127G>T, ENST00000635500.1:n.95G>T, NC_000012.12:g.102912832C>A, CM000674.2:g.102912832C>A, NC_000012.11:g.103306610C>A, CM000674.1:g.103306610C>A, NC_000012.10:g.101830740C>A, NG_008690.1:g.9771G>T, NG_008690.2:g.50579G>T, NM_000277.2(PAH):c.127G>T (p.Glu43Ter) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Pathogenic PM2 [MET], PVS1 [MET], PP4 [MET] The c.127G>T (p.Glu43*) variant is a nonsense variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in 2 individuals with PKU (BH4 deficiency not excluded). (PP4; PMID: 26503515). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. 26503515 PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA16020729/MONDO:0009861/006 0.9971 Pathogenic Pathogenic InterVar: Pathogenic PVS1=1 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36164712 561222 G T NM_001754.4(RUNX1):c.1163C>A (p.Ser388Ter) 561222 CA410147908 NM_001754.4:c.1163C>A, NC_000021.9:g.34792415G>T, CM000683.2:g.34792415G>T, NC_000021.8:g.36164712G>T, CM000683.1:g.36164712G>T, NC_000021.7:g.35086582G>T, NG_011402.2:g.1197297C>A, LRG_482:g.1197297C>A, NM_001001890.2:c.1082C>A, LRG_482t1:c.1163C>A, XM_005261068.3:c.1127C>A, XM_005261069.3:c.971C>A, XM_011529766.1:c.1163C>A, XM_011529767.1:c.1124C>A, XM_011529768.1:c.932C>A, XM_005261069.4:c.971C>A, XM_011529766.2:c.1163C>A, XM_011529767.2:c.1124C>A, XM_011529768.2:c.932C>A, XM_017028487.1:c.1010C>A, ENST00000300305.7:c.1163C>A, ENST00000344691.8:c.1082C>A, ENST00000399240.5:c.890C>A, ENST00000437180.5:c.1163C>A, ENST00000482318.5:c.*753C>A, NM_001754.4(RUNX1):c.1163C>A (p.Ser388Ter) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Pathogenic BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PM4 [Unmet], PM1 [Unmet], PM5 [Unmet], BP7 [Unmet], BS3 [Unmet], BS4 [Unmet], BS1 [Unmet], PS3-Supporting [MET], PVS1-Strong [MET], PP3 [Unmet], PP1 [Unmet], PS4-Supporting [MET], PM6 [Unmet], PM2 [MET] The NM_001754.4:c.1163C>A (p.Ser388Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). Transactivation assays demonstrate enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 20846103). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 20846103). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2, PS3_Supporting, PS4_Supporting. 20846103, 20846103, 20846103, 20846103 Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410147908/MONDO:0011071/008 0.9941 Likely Pathogenic Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36259177 561233 T G NM_001754.4(RUNX1):c.314A>C (p.His105Pro) 561233 CA410203519 NM_001754.4:c.314A>C, NM_001001890.2:c.233A>C, NM_001122607.1:c.233A>C, LRG_482t1:c.314A>C, XM_005261068.3:c.278A>C, XM_005261069.3:c.314A>C, XM_011529766.1:c.314A>C, XM_011529767.1:c.275A>C, XM_011529768.1:c.275A>C, XM_011529770.1:c.314A>C, XR_937576.1:n.493A>C, XM_005261069.4:c.314A>C, XM_011529766.2:c.314A>C, XM_011529767.2:c.275A>C, XM_011529768.2:c.275A>C, XM_011529770.2:c.314A>C, XM_017028487.1:c.161A>C, XR_937576.2:n.540A>C, ENST00000300305.7:c.314A>C, ENST00000344691.8:c.233A>C, ENST00000358356.9:c.233A>C, ENST00000399237.6:c.278A>C, ENST00000399240.5:c.233A>C, ENST00000437180.5:c.314A>C, ENST00000455571.5:c.275A>C, ENST00000482318.5:c.59-6167A>C, NC_000021.9:g.34886880T>G, CM000683.2:g.34886880T>G, NC_000021.8:g.36259177T>G, CM000683.1:g.36259177T>G, NC_000021.7:g.35181047T>G, NG_011402.2:g.1102832A>C, LRG_482:g.1102832A>C, NM_001754.4(RUNX1):c.314A>C (p.His105Pro) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Likely Pathogenic BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PM1-Supporting [MET], PS1 [Unmet], PS3 [Unmet], PM4 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PM5-Supporting [MET], PP3 [MET], PP1 [Unmet], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.314A>C (p.His105Pro) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score >0.75 (0.953) (PP3). This variant is a missense change at the same residue (p.His105Pro) where a different missense change has been previously established as a likely pathogenic variant (NM_001754.4:c.315C>A (p.His105Glu)) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; SCV000807773.1). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2, PP3, PM1_supporting, PM5_supporting, PS4_supporting. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410203519/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36252860 561243 C T NM_001754.4(RUNX1):c.502G>A (p.Gly168Arg) 561243 CA410202479 NM_001754.4:c.502G>A, NC_000021.9:g.34880563C>T, CM000683.2:g.34880563C>T, NC_000021.8:g.36252860C>T, CM000683.1:g.36252860C>T, NC_000021.7:g.35174730C>T, NG_011402.2:g.1109149G>A, LRG_482:g.1109149G>A, NM_001001890.2:c.421G>A, NM_001122607.1:c.421G>A, LRG_482t1:c.502G>A, XM_005261068.3:c.466G>A, XM_005261069.3:c.502G>A, XM_011529766.1:c.502G>A, XM_011529767.1:c.463G>A, XM_011529768.1:c.463G>A, XM_011529770.1:c.502G>A, XR_937576.1:n.681G>A, XM_005261069.4:c.502G>A, XM_011529766.2:c.502G>A, XM_011529767.2:c.463G>A, XM_011529768.2:c.463G>A, XM_011529770.2:c.502G>A, XM_017028487.1:c.349G>A, XR_937576.2:n.728G>A, ENST00000300305.7:c.502G>A, ENST00000344691.8:c.421G>A, ENST00000358356.9:c.421G>A, ENST00000399237.6:c.466G>A, ENST00000399240.5:c.421G>A, ENST00000437180.5:c.502G>A, ENST00000482318.5:c.*92G>A, NM_001754.4(RUNX1):c.502G>A (p.Gly168Arg) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BA1 [Unmet], BP4 [Unmet], BP2 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PM1-Supporting [MET], PM5 [Unmet], PM4 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], PP3 [MET], PP1 [Unmet], PVS1 [Unmet], PM2 [MET], PM6 [Unmet] The NM_001754.4:c.502G>A (p.Gly168Arg) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score >0.75 (0.947) (PP3). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2, PP3, PM1_supporting. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410202479/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 21 36231852 561246 T G NM_001754.4(RUNX1):c.532A>C (p.Thr178Pro) 561246 CA410208110 NM_001754.4:c.532A>C, NM_001001890.2:c.451A>C, NM_001122607.1:c.451A>C, LRG_482t1:c.532A>C, XM_005261068.3:c.496A>C, XM_005261069.3:c.532A>C, XM_011529766.1:c.532A>C, XM_011529767.1:c.493A>C, XM_011529768.1:c.493A>C, XM_011529770.1:c.532A>C, XR_937576.1:n.711A>C, XM_005261069.4:c.532A>C, XM_011529766.2:c.532A>C, XM_011529767.2:c.493A>C, XM_011529768.2:c.493A>C, XM_011529770.2:c.532A>C, XM_017028487.1:c.379A>C, XR_937576.2:n.758A>C, ENST00000300305.7:c.532A>C, ENST00000344691.8:c.451A>C, ENST00000358356.9:c.451A>C, ENST00000399237.6:c.496A>C, ENST00000399240.5:c.451A>C, ENST00000437180.5:c.532A>C, ENST00000467577.1:n.24A>C, ENST00000482318.5:c.*122A>C, NC_000021.9:g.34859555T>G, CM000683.2:g.34859555T>G, NC_000021.8:g.36231852T>G, CM000683.1:g.36231852T>G, NC_000021.7:g.35153722T>G, NG_011402.2:g.1130157A>C, LRG_482:g.1130157A>C, NM_001754.4(RUNX1):c.532A>C (p.Thr178Pro) RUNX1 hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome MONDO:0011071 Autosomal dominant inheritance Uncertain Significance BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PM1-Supporting [MET], PM5 [Unmet], PM4 [Unmet], BP7 [Unmet], BS3 [Unmet], BS1 [Unmet], BS4 [Unmet], PP3 [MET], PP1 [Unmet], PS4-Supporting [MET], PM2 [MET], PM6 [Unmet], PVS1 [Unmet] The NM_001754.4:c.532A>C (p.Thr178Pro) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score >0.75 (0.971) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; SCV000807789.1). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2, PP3, PS4_ supporting, PM1_supporting. Myeloid Malignancy VCEP https://www.clinicalgenome.org/site/assets/files/3833/clingen_myelomalig_acmg_specifications_v1.pdf false https://erepo.genome.network/evrepo/ui/classification/CA410208110/MONDO:0011071/008 0.8121 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[1, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103310906 585206 C G NM_000277.2(PAH):c.3G>C (p.Met1Ile) 585206 CA386303909 NM_000277.2:c.3G>C, NC_000012.12:g.102917128C>G, CM000674.2:g.102917128C>G, NC_000012.11:g.103310906C>G, CM000674.1:g.103310906C>G, NC_000012.10:g.101835036C>G, NG_008690.1:g.5475G>C, NG_008690.2:g.46283G>C, NM_000277.1:c.3G>C, XM_011538422.1:c.3G>C, NM_001354304.1:c.3G>C, XM_017019370.2:c.3G>C, NM_000277.3:c.3G>C, ENST00000307000.7:c.-145G>C, ENST00000546844.1:c.3G>C, ENST00000547319.1:n.314G>C, ENST00000549111.5:n.99G>C, ENST00000551337.5:c.3G>C, ENST00000551988.5:n.92G>C, ENST00000553106.5:c.3G>C, ENST00000635500.1:n.29-4230G>C, NM_000277.2(PAH):c.3G>C (p.Met1Ile) PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Pathogenic PM2 [MET], PVS1 [MET], PM5 [Unmet], PP4 [Unmet], PS1 [Unmet] The c.3G>C (p.Met1Ile) variant in PAH is a null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant is absent in population databases (PM2). This variant has not been reported in an affected individual in the literature to our knowledge. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PVS1. PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ false https://erepo.genome.network/evrepo/ui/classification/CA386303909/MONDO:0009861/006 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 3 Uncertain Significance 13 20763044 585322 A T NM_004004.5:c.677T>A 585322 CA387460663 NM_004004.5:c.677T>A, NC_000013.11:g.20188905A>T, CM000675.2:g.20188905A>T, NC_000013.10:g.20763044A>T, CM000675.1:g.20763044A>T, NC_000013.9:g.19661044A>T, NG_008358.1:g.9071T>A, XM_011535049.1:c.677T>A, XM_011535049.2:c.677T>A, NM_004004.6:c.677T>A, ENST00000382844.1:c.677T>A, ENST00000382848.4:c.677T>A GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PM6 [Unmet], PVS1 [Unmet], BS2 [Unmet], PP1 [Unmet], PP4 [Unmet], PP3 [Unmet], BP3 [Unmet], BP4 [Unmet], BP2 [Unmet], BA1 [Unmet], PS1 [Unmet], PS3 [Unmet], PS4 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM3 [Unmet], PM1 [Unmet], BP5 [Unmet], BP7 [Unmet], BS1 [Unmet], BS4 [Unmet] The c.677T>A (p.Val226Asp) variant in GJB2 has been identified in a heterozygous state in one Mongolian individual with sensorineural hearing loss (PS4 not met; PMID: 20201936). This variant was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2. 20201936 Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-27 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA387460663/MONDO:0019497/005 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 13 20763068 585327 C T NM_004004.5:c.653G>A 585327 CA6904216 NM_004004.5:c.653G>A, NC_000013.11:g.20188929C>T, CM000675.2:g.20188929C>T, NC_000013.10:g.20763068C>T, CM000675.1:g.20763068C>T, NC_000013.9:g.19661068C>T, NG_008358.1:g.9047G>A, XM_011535049.1:c.653G>A, XM_011535049.2:c.653G>A, NM_004004.6:c.653G>A, ENST00000382844.1:c.653G>A, ENST00000382848.4:c.653G>A GJB2 nonsyndromic genetic deafness MONDO:0019497 Autosomal recessive inheritance Uncertain Significance PM2 [MET], PVS1 [Unmet], PM6 [Unmet], BS2 [Unmet], PP3 [MET], PP1 [Unmet], PP4 [Unmet], BA1 [Unmet], BP4 [Unmet], BP3 [Unmet], BP2 [Unmet], PS1 [Unmet], PS4 [Unmet], PS3 [Unmet], PS2 [Unmet], PM5 [Unmet], PM4 [Unmet], PM1 [Unmet], PM3 [Unmet], BS1 [Unmet], BS4 [Unmet], BP7 [Unmet], BP5 [Unmet] The p.Cys218Tyr variant in GJB2 was identified in 0.002% (2/109924) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). Computational prediction tools and conservation analysis suggest that the p.Cys218Tyr variant may impact the protein (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2, PP3. Hearing Loss VCEP https://submit.ncbi.nlm.nih.gov/ft/byid/vroiax8b/hearing_loss_acmg_specifications_v1_2018.pdf 2018-09-10 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6904216/MONDO:0019497/005 0.4999 VUS Uncertain significance InterVar: Uncertain significance PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 1, 0, 0, 0, 0, 0] PP=[0, 0, 1, 0, 0, 0] BA1=0 BS=[0, 0, 0, 0, 0] BP=[0, 0, 0, 0, 0, 0, 0, 0] 2 Uncertain Significance 12 103246663 590340 G A NM_000277.1:c.772C>T 590340 CA6748843 NM_000277.1:c.772C>T, NC_000012.12:g.102852885G>A, CM000674.2:g.102852885G>A, NC_000012.11:g.103246663G>A, CM000674.1:g.103246663G>A, NC_000012.10:g.101770793G>A, NG_008690.1:g.69718C>T, NG_008690.2:g.110526C>T, XM_011538422.1:c.772C>T, NM_000277.2:c.772C>T, NM_001354304.1:c.772C>T, NM_000277.3:c.772C>T, ENST00000307000.7:c.757C>T, ENST00000549247.6:n.531C>T, ENST00000553106.5:c.772C>T PAH phenylketonuria MONDO:0009861 Autosomal recessive inheritance Likely Benign BP7 [MET], BS1 [MET], PM2 [Unmet] PAH-specific ACMG/AMP criteria applied: BS1: > PAH specific guidelines of AF-0.0002 (0.02%); BP7: No deleterious effect predicted.. In summary this variant meets criteria to be classified as likely benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BP7). PAH VCEP https://www.clinicalgenome.org/working-groups/clinical-domain/inborn-errors-of-metabolism-clinical-domain-working-group/pah-variant-curation-expert-panel/ 2018-08-13 2018-12-10 false https://erepo.genome.network/evrepo/ui/classification/CA6748843/MONDO:0009861/006 0.025 VUS Likely benign InterVar: Likely benign PVS1=0 PS=[0, 0, 0, 0, 0] PM=[0, 0, 0, 0, 0, 0, 0] PP=[0, 0, 0, 0, 0, 0] BA1=0 BS=[1, 0, 0, 0, 0] BP=[0, 0, 0, 1, 0, 0, 1, 0] 2 Uncertain Significance