ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1522C>T (p.Gln508Ter) (rs730880544)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158098 SCV000208033 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing The Q508X variant in the MYBPC3 gene has not been reported as a pathogenic variant or as a benign variant to our knowledge. This variant has been observed in one individual at GeneDx with a clinical diagnosis of HCM. The Q508X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay, Furthermore, many other nonsense variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014). Finally, the Q508X pathogenic variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Invitae RCV000705415 SCV000834411 pathogenic Hypertrophic cardiomyopathy 2018-08-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln508*) 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 not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 180941). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158098 SCV000280216 likely pathogenic not provided 2012-12-12 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. MYBPC3 p.Gln508Ter Given that this type of protein-truncating variant in MYBPC3 is a common mechanism for disease in HCM, (reviewed below) we consider this variant likely disease causing. The specific variant is novel and has not been seen in any other cases of HCM. Other nonsense variants have been reported in association with disease in this gene (Stenson P et al., 2009 and Pan et al 2012).

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