ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3372C>A (p.Cys1124Ter) (rs727504289)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619606 SCV000740242 pathogenic Cardiovascular phenotype 2017-10-20 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)
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769308 SCV000900686 pathogenic Cardiomyopathy 2015-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000413211 SCV000490642 pathogenic not provided 2017-11-30 criteria provided, single submitter clinical testing The C1124X variant in the MYBPC3 gene has been reported in association with HCM (Van Driest et al., 2004;Bashyam et al., 2012). Bashyam et al. (2012) describe an Indian boy with HCM at 3-years-old, though hisheterozygous mother and sibling remained asymptomatic. The C1124X variant is predicted to cause loss of normalprotein function either by protein truncation or nonsense-mediated mRNA decay. Other downstream nonsense variantsin the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stensonet al., 2014), indicating that loss of function is a known disease mechanism. Furthermore, this variant is not observedin large population cohorts (Lek et al., 2016).
Invitae RCV000808027 SCV000948111 pathogenic Hypertrophic cardiomyopathy 2018-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys1124*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs727504289, ExAC 0.01%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 15519027). ClinVar contains an entry for this variant (Variation ID: 177701). 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 RCV000808027 SCV000203961 pathogenic Hypertrophic cardiomyopathy 2014-08-07 criteria provided, single submitter clinical testing The Cys1124X variant in MYBPC3 has been reported in 1 individual with HCM (Van D riest 2004). This variant was absent from large population studies. This nonsens e variant leads to a premature termination codon at position 1124, which is pred icted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets our criteria to be classified as pathogenic (http:/ / based on the predicted impact of the variant.

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