Submissions for variant NM_000257.4(MYH7):c.5740G>A (p.Glu1914Lys)

dbSNP: rs397516254

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000035983	SCV000564463	likely pathogenic	Primary dilated cardiomyopathy	2021-03-22	reviewed by expert panel	curation	The c.5740G>A (p.Glu1914Lys) variant in MYH7 has been reported in at least 6 individuals with complex cardiomyopathy presentations, including predominantly dilated cardiomyopathy, features of LVNC, and restrictive physiology with early-onset in multiple instances (Lakdawala 2012 PMID: 22464770; Pugh 2014 PMID: 24503780; Lamont 2015 PMID: 20301606; Walsh 2017 PMID: 27532257; Wang 2017 PMID: 28855170; Miura 2019 PMID: 30996762). This variant segregated with disease in 2 affected siblings from 1 family (Miura 2019 PMID: 30996762); however this data is currently insufficient to apply PP1. This variant has been confirmed de novo occurrence in 2 of the above reported individuals with additional features of myopathy (PS2; Lamont 2014 PMID24664454). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). 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 dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PS2; PM2; PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035983	SCV000059635	pathogenic	Primary dilated cardiomyopathy	2016-01-29	criteria provided, single submitter	clinical testing	The p.Glu1914Lys variant in MYH7 has been previously identified in 3 individuals with childhood onset of DCM and was de novo in two of them with parental relati onships confirmed (Lakdawala 2012, Lamont 2014, Pugh 2014). It was absent from l arge population studies. This variant was predicted to be pathogenic using a com putational tool clinically validated by our laboratory. This tool's pathogenic p rediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic.
Baylor Genetics	RCV001329735	SCV001521255	pathogenic	Dilated cardiomyopathy 1S	2020-02-19	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV002510774	SCV002822117	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	MYH7: PS4, PM1, PM2, PP2, PP3
Invitae	RCV002513365	SCV003442268	pathogenic	Hypertrophic cardiomyopathy	2023-05-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 43088). This missense change has been observed in individual(s) with dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or additional features of skeletal myopathy (PMID: 22464770, 24664454, 27532257, 28855170, 30996762). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1914 of the MYH7 protein (p.Glu1914Lys).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149624	SCV003838096	likely pathogenic	Cardiomyopathy	2022-03-18	criteria provided, single submitter	clinical testing
Neurogenetics Laboratory, Royal Perth Hospital	RCV000132760	SCV000119911	pathogenic	Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2013-01-01	no assertion criteria provided	clinical testing
GeneReviews	RCV000192205	SCV000223112	not provided	MYH7-related skeletal myopathy		no assertion provided	literature only	Associated with cardiac transplant at age 3 and 3.5 yrs