Submissions for variant NM_000257.4(MYH7):c.1477A>G (p.Met493Val)

dbSNP: rs730880875

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158807	SCV000208742	likely pathogenic	not provided	2021-04-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 181349; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24093860, 28606303, 23816408, 27532257, 32492895, 17599605)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213209	SCV000272032	likely pathogenic	Hypertrophic cardiomyopathy	2019-02-26	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Ambry Genetics	RCV000622058	SCV000740192	likely pathogenic	Cardiovascular phenotype	2022-11-23	criteria provided, single submitter	clinical testing	The p.M493V variant (also known as c.1477A>G), located in coding exon 13 of the MYH7 gene, results from an A to G substitution at nucleotide position 1477. The methionine at codon 493 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in individuals reported to have hypertrophic cardiomyopathy (HCM) (Meyer T et al. Gene. 2013 Sep;527:416-20; Walsh R et al. Genet Med. 2017;19:192-203). In addition, other alterations at the same codon (p.M493I and p.M493L) have also been reported in association with cardiomyopathy (Marsiglia JD et al. Am Heart J. 2013;(1):416-20; Homburger Proc Natl Acad Sci USA. 2016 06;113(24):6701-6; Walsh R et al. Genet Med. 2017;19:192-203; Kubo T et al. Am Coll Cardiol. 2007;49(25):2419-26). Furthermore, internal structural analysis indicates this alteration is located in the myosin head region, and would be expected to disrupt the stroke motion of the protein (Gourinath S et al. Structure. 2003;11(12):1621-7; Risal D et al. Proc Natl Acad Sci USA. 2004;101(24):8930-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000158807	SCV001447396	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV000213209	SCV003442318	pathogenic	Hypertrophic cardiomyopathy	2023-04-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met493 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 24093860, 28615295), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 181349). This missense change has been observed in individuals with autosomal dominant MYH7-related cardiomyopathy (PMID: 17599605, 23816408, 27532257, 32492895; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 493 of the MYH7 protein (p.Met493Val).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317105	SCV004020524	likely pathogenic	Cardiomyopathy	2023-06-09	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.1477A>G (p.Met493Val) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251488 control chromosomes (gnomAD). c.1477A>G has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Meyer_2013, Walsh_2017, Kim)2020, Nafissi_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32492895, 23816408, 36136372, 27532257). Five ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and four as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.