Submissions for variant NM_000257.4(MYH7):c.1805A>G (p.Asn602Ser)

dbSNP: rs730880880

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158817	SCV000208752	likely pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	Observed in individuals with HCM in the published literature, including one individual that also harbored a pathogenic variant in another HCM-related gene (Marian et al., 1995; Page et al., 2012) and in patients with HCM referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7648684, 22267749, 33495597, 25132132, 27532257, 29300372)
Ambry Genetics	RCV000619801	SCV000740188	uncertain significance	Cardiovascular phenotype	2022-08-17	criteria provided, single submitter	clinical testing	The p.N602S variant (also known as c.1805A>G), located in coding exon 14 of the MYH7 gene, results from an A to G substitution at nucleotide position 1805. The asparagine at codon 602 is replaced by serine, 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 alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited and additional alterations in other cardiac-related genes were identified in some cases (Marian AJ et al. Circulation, 1995 Sep;92:1336-47; Page SP et al. Circ Cardiovasc Genet, 2012 Apr;5:156-66; Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7; Harper AR et al. Nat Genet, 2021 02;53:135-142). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000628886	SCV000749794	pathogenic	Hypertrophic cardiomyopathy	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 602 of the MYH7 protein (p.Asn602Ser). This variant is present in population databases (rs730880880, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 181354). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000158817	SCV003817686	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing