ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.721G>C (p.Val241Leu) (rs886039000)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000251235 SCV000319569 uncertain significance Cardiovascular phenotype 2015-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
GeneDx RCV000480673 SCV000565270 likely pathogenic not provided 2015-02-12 criteria provided, single submitter clinical testing The V241L variant has not been published as a pathogenic variant or as a benign polymorphism to our knowledge. The V241L variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the V241L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is highly conserved in vertebrates. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, missense mutations in nearby residues (Y237H, Y237C, Y237S, R238H, E240D, S242P) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae RCV000693043 SCV000820897 uncertain significance Hypertrophic cardiomyopathy 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 241 of the MYBPC3 protein (p.Val241Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. 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: 263980). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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