Submissions for variant NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

dbSNP: rs121913629

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV001618212	SCV001842661	likely pathogenic	Hypertrophic cardiomyopathy	2021-03-22	reviewed by expert panel	curation	The c.2845G>A (p.Glu949Lys) variant in MYH7 has been reported in 12 individuals with HCM (PS4_Moderate; Watkins 1992 PMID:1552912; Walsh 2017 PMID:27532257; Zigova 2018 PMID:28815794; CHEO pers comm.). This variant segregated with disease in 1 affected relative with HCM (Watkins 1992 PMID:1552912); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has been reported as a de novo occurence in 1 child with RCM (PM6; Kapoor 2017 http://repository.ias.ac.in/114592/1/JPractCardiovascSci33143-8313497_230534.pdf). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM6; PM2; PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001618212	SCV000203860	likely pathogenic	Hypertrophic cardiomyopathy	2022-07-28	criteria provided, single submitter	clinical testing	The p.Glu949Lys variant in MYH7 has been reported in >11 individuals with hypertrophic cardiomyopathy (HCM) and as a de novo occurrence in 1 individual with restrictive cardiomyopathy (RCM) and segregated with disease in 1 affected individual from 1 family (Watkins 1992 PMID: 1552912, Kapoor 2017, Zigova 2017 PMID: 28815794, Walsh 2017 PMID: 27532257/LMM data). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant was classified as Likely Pathogenic on March 22, 2021 by the ClinGen-approved Cardiomyopathy Variant Curation expert panel (Variation ID 14093). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM6, PM2_Supporting, PP3.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770487	SCV000901931	uncertain significance	Cardiomyopathy	2016-04-14	criteria provided, single submitter	clinical testing
Invitae	RCV001618212	SCV004296261	uncertain significance	Hypertrophic cardiomyopathy	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 949 of the MYH7 protein (p.Glu949Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 1552912, 27532257, 28815794). ClinVar contains an entry for this variant (Variation ID: 14093). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003996097	SCV004840111	likely pathogenic	Primary dilated cardiomyopathy	2023-12-11	criteria provided, single submitter	clinical testing	The c.2845G>A (p.Glu949Lys) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in at least twelve individuals affected with Hypertrophic Cardiomyopathy (HCM) (ClinGen Expert Panel review [ClinVar ID: 14093], PMID:1552912, 27532257, 28815794, 1552912). This variant has been reported as de novo status in a proband with restrictive cardiomyopathy (ClinVar ID: 14093, PMID: NA). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.909). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel (ClinVar ID: 14093). Therefore, the c.2845G>A (p.Glu949Lys) variant in the MYH7 gene is classified as likely pathogenic.
OMIM	RCV000015149	SCV000035406	pathogenic	Hypertrophic cardiomyopathy 1	1992-04-23	no assertion criteria provided	literature only