ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2670G>A (p.Trp890Ter) (rs397515982)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000197345 SCV000059169 pathogenic Hypertrophic cardiomyopathy 2017-11-28 criteria provided, single submitter clinical testing The p.Trp890X variant in MYBPC3 has been reported in >10 individuals with HCM an d segregated with disease in at least 5 affected relatives (Van Driest 2004, Ehl ermann 2008, LMM data). It was absent from large population studies. This varian t has also been reported by other clinical laboratories in ClinVar (Variation ID 42650). This nonsense variant leads to a premature termination codon at positio n 890, which is predicted to lead to a truncated or absent protein. Heterozygous loss of MYBPC3 function is an established disease mechanism in HCM. In summary, the p.Trp890X variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based on upon segregation studies and the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PS4, PP1_Moderate.
GeneDx RCV000158180 SCV000208115 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing The W890X pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (Van Driest et al., 2004; Ehlermann et al., 2008; Brito et al., 2012; Otsuka et al., 2012; Kapplinger et al., 2014). Otsuka et al. (2012) reported W890X in three siblings with HCM from the same family; however, the affected parent was unavailable for testing. In addition, Ehlermann et al. (2008) reported segregation of this variant with HCM in one affected relative. The W890X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Expression studies by Helms et al. (2014) demonstrated that the W890X transcript is subject to nonsense-mediated mRNA decay. Furthermore, other downstream nonsense variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014).
Invitae RCV000197345 SCV000253811 pathogenic Hypertrophic cardiomyopathy 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 890 (p.Trp890*). It is expected to result in an absent or disrupted protein product. Truncating variants in MYBPC3 are known to be pathogenic (PMID: 15114369, 18533079). This particular truncation has been reported in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 15519027, 22857948) and shown to segregate with disease in a family (PMID: 18957093). Furthermore, this variant has been reported in at least 8 individuals affected with HCM by a diagnostic lab (Variation ID: 42650). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000158180 SCV000747944 pathogenic not provided 2016-05-11 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158180 SCV000280242 likely pathogenic not provided no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Trp890Stop (c.3670G>A). Based on the data reviewed below we consider it likely disease causing. In total the variant has been seen in at least 4 unrelated cases with weak segregation data. This variant was initially reported in one individual with HCM by Van Driest S et al (2004) then in two more affected members of one family reported by Ehlermann P et al (2008). The Seidman group report on their program website that they have seen this variant in their cohort (Merk, Seidman et al 2004). Brito et al (2012) observed the variant in one individual in their Portuguese HCM cohort. This is a nonsense variant predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. Many other truncating or null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). In total the variant has not been seen in ~6700 published controls and publicly available general population sample. Van Driest et al (2004) report that p.Trp890Stop was not observed in 100 Caucasian and 100 African American presumably healthy individuals. Brito et al (2012) did not observe the variant in 100 control samples. GeneDx did not report internal control data. The variant is not listed in dbSNP or 1000 Genomes. In addition p.Trp890Stop is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of September 2012).

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