ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.999C>G (p.Tyr333Ter) (rs367947846)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000242648 SCV000318860 pathogenic Cardiovascular phenotype 2013-08-09 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 RCV000769355 SCV000900743 pathogenic Cardiomyopathy 2015-10-22 criteria provided, single submitter clinical testing
GeneDx RCV000414122 SCV000490637 pathogenic not provided 2019-01-16 criteria provided, single submitter clinical testing Although the Y333X variant, caused by a substitution of C>G at position c.999, in the MYBPC3 gene has not been reported as a pathogenic or as a benign polymorphism to our knowledge, another nonsense variant affecting this same residue (c.999 C>A) has been reported in one individual with HCM (Kassem H et al., 2013). In addition, Y333X has been reported as a pathogenic variant in one other individual tested for HCM at GeneDx and in multiple individuals tested for HCM at the Laboratory for Molecular Medicine (Landrum M et al., 2014). This variant results in the loss of 942 amino acids from the C-terminus and is predicted to cause loss of normal protein function by either protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson P et al., 2014). Finally, the Y333X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Y333X in the MYBPC3 gene is interpreted as a pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154309 SCV000203969 pathogenic Hypertrophic cardiomyopathy 2015-10-29 criteria provided, single submitter clinical testing The p.Tyr333X variant in MYBPC3 has been reported in 3 individuals with HCM, seg regated with disease in 1 affected relative from 1 family (Kassem 2013, LMM unpu blished data) and was absent from large population studies. This nonsense varian t leads to a premature termination codon at position 333, which is predicted to lead to a truncated protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our cri teria to be classified as pathogenic for HCM in an autosomal dominant manner.

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