ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3697C>T (p.Gln1233Ter) (rs397516037)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000588073 SCV000737358 pathogenic Cardiovascular phenotype 2017-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Blueprint Genetics RCV000208463 SCV000264042 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-04 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000168193 SCV000886773 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000035610 SCV000292232 likely pathogenic Familial hypertrophic cardiomyopathy 4 2015-07-30 criteria provided, single submitter clinical testing This mutation in the MYBPC3 gene was identified in a female patient with hypertrophic cardiomyopathy.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678715 SCV000804884 pathogenic Left ventricular hypertrophy 2017-08-28 no assertion criteria provided clinical testing
GeneDx RCV000158254 SCV000208189 pathogenic not provided 2018-10-11 criteria provided, single submitter clinical testing The Q1233X pathogenic variant in the MYBPC3 gene has been previously reported in numerous individuals with HCM (Erdmann et al., 2001; Ingles et al., 2005; Zeller et al., 2006; Ehlermann et al., 2008; Fokstuen et al., 2008; Geier et al., 2008; Roncarati et al., 2011; Toth et al., 2011) and has been described to segregate with disease in several families (Erdmann et al., 2001; Zeller et al., 2006; Ehlermann et al., 2008; Geier et al., 2008; Toth et al., 2011). Furthermore, Q1233X has been seen in multiple individuals referred for cardiomyopathy genetic testing at GeneDx, and is classified in ClinVar as pathogenic or likely pathogenic in association with HCM by five other clinical laboratories (ClinVar SCV000059261.4, SCV000218858.3, SCV000219828.2, SCV000264042.1, SCV000292232.1; Landrum et al., 2016). The Q1233X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Many other nonsense variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Moreover, Q1233X is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Integrated Genetics/Laboratory Corporation of America RCV000588073 SCV000696331 pathogenic Cardiovascular phenotype 2016-06-06 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000168193 SCV000218858 pathogenic Hypertrophic cardiomyopathy 2018-12-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1233*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754). ClinVar contains an entry for this variant (Variation ID: 42735). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000168193 SCV000059261 pathogenic Hypertrophic cardiomyopathy 2011-11-18 criteria provided, single submitter clinical testing The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, Ehlermann 2008, LMM data). This variant has also been identified in 1/66626 Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs397516037). This nonsense variant leads to a premature term ination codon at position 1233, which is predicted to lead to a truncated or abs ent protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets cr iteria to be classified as pathogenic for HCM in an autosomal dominant manner.

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