ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2179G>A (p.Val727Met) (rs564378953)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158140 SCV000208075 likely pathogenic not provided 2015-07-30 criteria provided, single submitter clinical testing p.Val727Met (V727M) GTG>ATG: c.2179 G>A in exon 23 of the MYBPC3 gene (NM_000256.3) The Val727Met variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Val727Met results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. In silico analysis predicts Val727Met is probably damaging to the protein structure/function. Mutations in nearby residues (Arg726Cys, Arg733Cys) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the Val727Met variant was not observed in approximately 6,000 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, while Val727Met in the MYBPC3 gene is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM,DCM panel(s).
Ambry Genetics RCV000621359 SCV000736873 uncertain significance Cardiovascular phenotype 2017-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000628990 SCV000749900 uncertain significance Hypertrophic cardiomyopathy 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 727 of the MYBPC3 protein (p.Val727Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs564378953, ExAC 0.01%). This variant has been observed in two individuals with hypertrophic cardiomyopathy (PMID: 25351510, 28790153). However, in one of these individuals a pathogenic allele was also identified in MYBPC3. ClinVar contains an entry for this variant (Variation ID: 180964). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Blueprint Genetics RCV000158140 SCV000927374 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing

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