Submissions for variant NM_000257.4(MYH7):c.2123G>C (p.Gly708Ala)

dbSNP: rs397516134

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035765	SCV000059416	likely pathogenic	Hypertrophic cardiomyopathy	2017-06-06	criteria provided, single submitter	clinical testing	The p.Gly708Ala variant in MYH7 has been reported in 3 individuals with HCM, 1 i ndividual with LVNC, and segregated with disease in 1 affected relative (Helms 2 014, LMM data). This variant has been reported in ClinVar (Variation ID: 42882). This variant is absent from large population studies. Glycine (Gly) at position 708 is highly conserved in mammals and across evolutionarily distant species an d the change to alanine (Ala) was predicted to be pathogenic using a computation al tool clinically validated by our laboratory. This tool's pathogenic predictio n is estimated to be correct 94% of the time (Jordan 2011). Of note, this varian t lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Wa lsh 2016). In summary, although additional studies are required to fully establi sh its clinical significance, the p.Gly708Ala variant is likely pathogenic.
GeneDx	RCV000158509	SCV000208444	likely pathogenic	not provided	2021-02-09	criteria provided, single submitter	clinical testing	Identified in patients with HCM referred for genetic testing at GeneDx and in the published literature (Homburger et al., 2016; Walsh et al., 2017; Helms et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 42882; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25031304, 27532257, 27247418)
Invitae	RCV000035765	SCV002128581	likely pathogenic	Hypertrophic cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 708 of the MYH7 protein (p.Gly708Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or left ventricular noncompaction (PMID: 25031304, 27532257, 33500567; Invitae). ClinVar contains an entry for this variant (Variation ID: 42882). 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%. 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.