Submissions for variant NM_000257.4(MYH7):c.2167C>G (p.Arg723Gly)

dbSNP: rs121913630

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000227196	SCV000564424	pathogenic	Hypertrophic cardiomyopathy	2016-12-15	reviewed by expert panel	curation	The c.2167C>G (p.Arg723Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PS4; PMID:11113006; PMID:19150014; PMID:17097032; Partners LMM ClinVar SCV000059422.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >20 affected individuals (PP1_Strong; PMID:11113006). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2167C>T p.Arg723Cys - ClinVar Variation ID 14095). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000227196	SCV000059422	pathogenic	Hypertrophic cardiomyopathy	2017-05-11	criteria provided, single submitter	clinical testing	The p.Arg723Gly variant in MYH7 has been reported in the literature in at least four families with HCM, progressive CHF, and sudden cardiac death, segregated wi th disease in >20 affected relatives, and was absent from 400 control chromosome s (Enjuto 2000, Yang 2006). This variant is also absent from large population st udies. This variant is reported in ClinVar (Variant ID 42885) and classified as pathogenic by an expert panel. This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathog enic prediction is estimated to be correct 94% of the time (Jordan 2011). Of not e, this variant lies in the head region of the protein. Missense variants in thi s region have been reported and statistically indicated to be more likely to cau se disease (Walsh 2016). In summary, the p.Arg723Gly variant meets our criteria to be classified as pathogenic based upon segregation studies, absence in contro ls, and computational assessment.
GeneDx	RCV000158837	SCV000208772	pathogenic	not provided	2017-02-02	criteria provided, single submitter	clinical testing	The R723G pathogenic variant in the MYH7 gene has been reported in many individuals with HCM (Enjuto et al., 2000; Yang et al., 2006; Gacia-Castro et al., 2009; Tripathi et al., 2011; Zheng et al., 2010; Coto et al., 2012; Marsiglia et al., 2013; Gomez et al., 2014). In multiple unrelated cases, the variant segregated with disease throughout large multi-generational families (Enjuto et al., 2000; Yang et al., 2010; Zheng et al., 2010). Allelic expression studies on skeletal and myocardium tissue from one family showed a larger R237G load compared to the wild-type allele, and load seemed to be correlated with disease severity (Enjuto et al., 2000; Tripathi et al., 2011). Additionally, the R723G variant has been reported as a likely pathogenic or pathogenic variant in multiple individuals with HCM who were referred for genetic testing at GeneDx and other clinical laboratories (ClinVar SCVSCV000256127.1, SCV000284260.1, SCV000059422.4; Landrum et al., 2016). Two variants at the same residue (R723C, R723H) are also reported as likely pathogenic or pathogenic.The R723G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R723G variant 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 arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, analysis of skeletal muscle and cardiomyocytes from individuals harboring the R723G variant showed myofibrillar deficiency and disarray with reduced calcium sensitivity and increased stiffness of the myosin-head, resulting in decreased force generation for cardiomyocytes, in particular (Seebohm et al., 2009; Kraft et al., 2013; Brenner et al., 2014). It is suggested that these effects activate stretch-sensitive signaling and, in turn, results in cardiac remodeling, the hallmark of HCM.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201494	SCV000256127	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing
Invitae	RCV000227196	SCV000284260	pathogenic	Hypertrophic cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 723 of the MYH7 protein (p.Arg723Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 11113006, 17097032, 19150014, 20865685, 24093860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42885). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 19651039, 23318932, 25346696). This variant disrupts the p.Arg723 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1430197, 9829907, 12707239, 21835320). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000035771	SCV000747952	pathogenic	Primary familial hypertrophic cardiomyopathy	2016-06-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000158837	SCV000928023	pathogenic	not provided	2018-10-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000158837	SCV001715069	pathogenic	not provided	2020-08-18	criteria provided, single submitter	clinical testing	PP1_Strong, PS4, PS3, PM1, PM2, PM5, PP3