Submissions for variant NM_000257.4(MYH7):c.2792A>G (p.Glu931Gly)

dbSNP: rs730880760

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158576	SCV000208511	pathogenic	not provided	2013-08-05	criteria provided, single submitter	clinical testing	p.Glu931Gly (GAG>GGG): c.2792 A>G in exon 23 of the MYH7 gene (NM_000257.2). While the Glu931Gly mutation in the MYH7 gene has not been reported to our knowledge, a mutation affecting this same residue, Glu931Lys, has been reported in association with HCM (Van Driest S et al., 2004). Additionally, mutations in nearby residues (Glu930Gln, Glu930Lys, Met932Lys, Glu935Lys) have been reported in association with HCM, further supporting the functional importance of this residue and this region of the protein. Glu931Gly results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a non-polar Glycine at a position that is conserved across species. In silico analysis predicts Glu931Gly is damaging to the protein structure/function. Furthermore, Glu931Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Glu931Gly in the MYH7 gene is interpreted as a likely disease-causing mutation. The variant is found in HCM panel(s).
Invitae	RCV000541761	SCV000623685	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 931 of the MYH7 protein (p.Glu931Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 181206). 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%. This variant disrupts the p.Glu931 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002433701	SCV002747346	uncertain significance	Cardiovascular phenotype	2022-08-24	criteria provided, single submitter	clinical testing	The p.E931G variant (also known as c.2792A>G), located in coding exon 21 of the MYH7 gene, results from an A to G substitution at nucleotide position 2792. The glutamic acid at codon 931 is replaced by glycine, an amino acid with 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 has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Harper AR et al. Nat Genet. 2021 02;53(2):135-142). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.