ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5071G>A (p.Val1691Met) (rs45464193)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208343 SCV000264096 uncertain significance Left ventricular noncompaction cardiomyopathy 2015-05-25 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769438 SCV000900831 uncertain significance Cardiomyopathy 2017-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000483083 SCV000565697 uncertain significance not specified 2016-08-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The V1691M variant was first reported in an individual with HCM and was absent from 200 control chromosomes (Richard et al., 2003). V1691M was also identified in an individual with familial DCM, however, segregation data were not reported (Hershberger et al., 2008). V1691M was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, though, it has been reported at a low frequency (1/1322 alleles, 0.08%) in individuals of African ancestry in the 1000 Genomes Project. The V1691M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, although this substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species, Methionine is not present in any species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000531386 SCV000623733 uncertain significance Hypertrophic cardiomyopathy 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1691 of the MYH7 protein (p.Val1691Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs45464193, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 12707239, 19412328, 27247418). ClinVar contains an entry for this variant (Variation ID: 222731). 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 tolerated, but these predictions have not been confirmed by published functional studies. 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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