ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2167C>G (p.Arg723Gly) (rs121913630)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics, RCV000158837 SCV000928023 pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing
ClinGen Inherited 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
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.
Invitae RCV000227196 SCV000284260 pathogenic Hypertrophic cardiomyopathy 2016-08-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 723 of the MYH7 protein (p.Arg723Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with hypertrophic cardiomyopathy (HCM) and has also been shown to segregate with disease in many multigenerational families (PMID: 11113006, 17097032, 19150014, 20865685, 24093860). Experimental studies performed using patients cardiac and skeletal muscle have shown that this missense change leads to an increase in resistance to elastic distortion of the myosin head domain and to changes in myosin Ca2+ sensitivity and maximum force production (PMID: 19651039, 23318932, 25346696). A different missense substitution at this codon (p.Arg723Cys) has been reported in many individuals affected with HCM and has been shown to segregate with disease in a large family and to occur de novo in another HCM family (PMID: 9829907, 12707239, 1430197, 21835320). This indicates that the arginine residue is important for MYH7 protein function. In summary, this is a rare missense change that has been shown to segregate with HCM in many families and to alter protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035771 SCV000059422 pathogenic Primary familial 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 with disease in >20 affected relatives, and was absent from 400 control chromosomes (Enjuto 2000, Yang 2006). This variant is also absent from large population studies. 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 pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Of note, this variant 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 (Walsh 2016). In summary, the p.Arg723Gly variant meets our criteria to be classified as pathogenic based upon segregation studies, absence in controls, and computational assessment.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000201494 SCV000256127 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
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

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