ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1157A>G (p.Tyr386Cys) (rs727503269)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000487451 SCV000564411 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.1157A>G (p.Tyr386Cys) variant in MYH7 has been identified as an unconfirmed de novo occurrence in a patient with hypertrophic cardiomyopathy (PM6; Partners LMM ClinVar SCV000199233.4). This variant was absent from large population studies (PM2; This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM6; PM1; PM2; PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151296 SCV000199233 pathogenic Restrictive cardiomyopathy; Left ventricular noncompaction; Hypertrophic cardiomyopathy 2013-08-23 criteria provided, single submitter clinical testing The Tyr386Cys variant in MYH7 has been identified in 2 infants with HCM addition al features (LNVC and RCM; Lakdawala 2012, LMM unpublished data) and was not ide ntified in large population studies. Of note, the variant appeared to have occur red de novo and in the absence of a family history of cardiomyopathy in both ins tances. As such, this variant meets our criteria to be classified as pathogenic ( based upon absence from controls and de novo occ urence.
GeneDx RCV000522095 SCV000617295 likely pathogenic not provided 2017-09-11 criteria provided, single submitter clinical testing The Y386C likely pathogenic variant in the MYH7 gene has been reported in association with cardiomyopathy (Lakdawala et al., 2012; Greenway et al., 2012; Walsh et al., 2017). The Y386C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y386C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, while a missense variant in the same residue (Y386H) has been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of this variant has not been definitively determined.

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