Submissions for variant NM_000257.4(MYH7):c.2222G>A (p.Gly741Glu)

dbSNP: rs1057520814

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429053	SCV000518150	likely pathogenic	not provided	2016-12-29	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic was identified in the MYH7 gene. The G741E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G741E variant 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. G741E 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 where only amino acids with similar properties to Glycine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, different pathogenic missense variants at the same residues (G741R, G741W) have been reported in the Human Gene Mutation Database and at GeneDx in association with HCM (Stenson et al., 2014), supporting the functional importance of this residue. However, to our knowledge no studies have been performed to determine the functional effect of the G741E variant.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381453	SCV001579836	pathogenic	Hypertrophic cardiomyopathy	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 741 of the MYH7 protein (p.Gly741Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MYH7-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 380277). 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 is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.