Submissions for variant NM_000257.4(MYH7):c.727C>T (p.Arg243Cys)

gnomAD frequency: 0.00001  dbSNP: rs397516265

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000629015	SCV000059648	uncertain significance	Hypertrophic cardiomyopathy	2021-11-19	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629015	SCV000749925	pathogenic	Hypertrophic cardiomyopathy	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 243 of the MYH7 protein (p.Arg243Cys). This variant is present in population databases (rs397516265, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21799269, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 43101). 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. This variant disrupts the p.Arg243 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18506004, 20965760, 21551322; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001188097	SCV001355065	likely pathogenic	Cardiomyopathy	2023-11-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 243 of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Experimental functional studies using human induced pluripotent stem cells have shown that this variant causes impaired cardiomyocyte relaxation and increased multinucleation (PMID: 33705529). This variant has been reported in at least six individuals affected with hypertrophic cardiomyopathy (PMID: 21799269, 27247418, 27532257, 30297972, 32815737, 32830170). This variant has been identified in 1/31404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256698	SCV001433101	likely pathogenic	Hypertrophic cardiomyopathy 1	2020-05-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001569534	SCV001793639	likely pathogenic	not provided	2023-08-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20350521, 21799269, 27247418, 27532257, 29121657, 25132132, 32830170, 33705529, 30297972, 35653365, 33487615, 29300372)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001188097	SCV002042702	likely pathogenic	Cardiomyopathy	2020-12-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381295	SCV002671525	likely pathogenic	Cardiovascular phenotype	2024-02-23	criteria provided, single submitter	clinical testing	The p.R243C variant (also known as c.727C>T), located in coding exon 6 of the MYH7 gene, results from a C to T substitution at nucleotide position 727. The arginine at codon 243 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in association with hypertrophic cardiomyopathy (HCM) (Hirota T et al. J Cardiol, 2010 Jul;56:59-65; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948; Ho CY et al. Circulation, 2018 Oct;138:1387-1398). 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). Another alteration at the same codon, p.R243H (c.728G>A), has been identified in multiple probands with left ventricular noncompaction cardiomyopathy (LVNC), dilated cardiomyopathy, and HCM and has been reported to segregate with disease (Klaassen S et al. Circulation, 2008 Jun;117:2893-901; Chang B et al. Mol. Genet. Metab., 2011 Feb;102:200-6; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722; Invitae pers. comm.; OMGL pers. comm.). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496549	SCV002780965	likely pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-07-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001569534	SCV004010268	likely pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MYH7: PM1, PM2, PS4:Moderate, PP3
All of Us Research Program, National Institutes of Health	RCV000629015	SCV004844794	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 243 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Experimental functional studies using human induced pluripotent stem cells have shown that this variant causes impaired cardiomyocyte relaxation and increased multinucleation (PMID: 33705529). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21799269, 27247418, 27532257, 30297972, 32815737, 32830170). This variant has been identified in 1/31404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001569534	SCV001798784	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001569534	SCV001931548	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001569534	SCV001957926	pathogenic	not provided		no assertion criteria provided	clinical testing