ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.493A>G (p.Met165Val) (rs730880839)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766401 SCV000208672 uncertain significance not provided 2017-04-04 criteria provided, single submitter clinical testing The Met165Val variant in the MYH7 gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. Met165Val results in a conservative amino acid substitution of one non-polar amino acid for another at a position that is conserved across species. In silico analysis predicts Met165Val is damaging to the protein structure/function. Variants in nearby residues (Tyr162Cys, Tyr162His, Tyr177Ile) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, Met165Val was not present in the 1000 Genomes database, and the NHLBI ESP Exome Variant Server reports Met165Val was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Color RCV001191621 SCV001359507 uncertain significance Cardiomyopathy 2019-07-15 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223786 SCV000280356 uncertain significance not specified 2012-08-22 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. p.Met165Val (M165V; c.493 A>G) in the MYH7 gene This variant is completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism. Variation at nearby residues in MYH7 has been associated with cardiomyopathy, supporting the functional importance of this region of the protein: Tyr162Cys, Tyr162His, Thr177Ile (HGMD via GeneDx). This is a conservative amino acid change from a nonpolar methionine to a nonpolar valine. The methionine at codon 165 is absolutely conserved across 32 vertebrate species examined. Some nearby residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign” with a score of 0.237. GeneDx reports that “in silico analysis predicts Met165Val is damaging to the protein structure/function.” In total this variant has not been seen in ~7500 individuals from publicly available population datasets, ~4679 of them ethnicity-matched to our Caucasian patient. No variation at this codon is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). No variation at this codon is present in dbSNP or in 1000 genomes (made up of 1092 individuals of various races, 379 of them with European backgrounds). GeneDx did not report controls.

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