ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1641_1642del (p.Tyr548fs) (rs398123279)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078449 SCV000110302 pathogenic not provided 2013-11-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000629016 SCV000198888 pathogenic Hypertrophic cardiomyopathy 2014-08-22 criteria provided, single submitter clinical testing The Tyr548fs variant in MYBPC3 has previously been reported in at least 1 indivi dual with HCM and was absent from 400 control chromosomes (Driest 2004). Data fr om large population studies is insufficient to assess the frequency of this vari ant. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 548 and leads to a premature terminat ion codon 19 amino acids downstream. This alteration is then predicted to lead t o a truncated or absent protein. Heterozygous loss of function of function of th e MYBPC3 gene is an established disease mechanism in HCM. In summary, this varia nt meets our criteria to be classified as pathogenic ( rsonalizedmedicine/LMM) based upon the predicted impact of the variant.
GeneDx RCV000078449 SCV000208283 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing The c.1641_1642delGT pathogenic variant in the MYBPC3 gene, also denoted as E546fs/19 due to alternate nomenclature, has been reported in multiple individuals in association with HCM (Van Driest et al., 2004; Berge et al., 2014). This variant has also been observed in other individuals referred for HCM genetic testing at GeneDx, and it is classified as a pathogenic/likely pathogenic variant in ClinVar by other clinical laboratories (SCV000110302.6, SCV000198888.3, SCV000264054.1; Landrum et al., 2016). The c.1641_1642delGT variant causes a shift in reading frame starting at codon tyrosine 548, changing it to a proline, and creating a premature stop codon at position 19 of the new reading frame, denoted p.Tyr548ProfsX19. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other frameshift variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1641_1642delGT variant has not been observed in large population cohorts (Lek et al., 2016).
Blueprint Genetics RCV000208043 SCV000264054 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-10-09 criteria provided, single submitter clinical testing
Invitae RCV000629016 SCV000749926 pathogenic Hypertrophic cardiomyopathy 2020-04-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr548Profs*19) 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 24111713, 28971120). This variant is also known as E546 fs/19 in the literature. ClinVar contains an entry for this variant (Variation ID: 92689). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.

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