Submissions for variant NM_000257.4(MYH7):c.1479G>A (p.Met493Ile)

dbSNP: rs730880876

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158808	SCV000208743	likely pathogenic	not provided	2020-09-18	criteria provided, single submitter	clinical testing	Reported in association with HCM, including at least one Brazilian patient with HCM; however, not all publications included coding DNA nomenclature (Marsiglia et al., 2013; Oliveira et al., 2015; Walsh et al., 2017); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27532257, 24093860, 25937619)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001349518	SCV001543869	pathogenic	Hypertrophic cardiomyopathy	2024-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 493 of the MYH7 protein (p.Met493Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 24093860, 27247418, 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 181350). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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: 23816408, 24093860, 28615295), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002390383	SCV002697084	uncertain significance	Cardiovascular phenotype	2022-10-13	criteria provided, single submitter	clinical testing	The p.M493I variant (also known as c.1479G>A), located in coding exon 13 of the MYH7 gene, results from a G to A substitution at nucleotide position 1479. The methionine at codon 493 is replaced by isoleucine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant and a different nucleotide change resulting in the same amino acid substitution (p.M493I, c.1479G>C) have been detected in hypertrophic cardiomyopathy (HCM) cohorts and in cohorts referred for HCM genetic testing (Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.