ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2146G>A (p.Gly716Arg) (rs121913638)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000233499 SCV000564420 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2146G>A (p.Gly716Arg) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:23074333; PMID:20641121; PMID:12084606; PMID:8282798; PMID:18953637; PMID:12707239; PMID:15358028; PMID:12975413; Partners LMM ClinVar SCV000059418.5; SHaRe consortium, PMID: 30297972). This variant has been identified as a de novo occurrence in 2 probands with hypertrophic cardiomyopathy (PM6; PMID:18953637; Partners LMM ClinVar SCV000059418.5). This variant segregated with disease in 11 affected individuals (PP1_Strong; PMID:8282798; PMID:20641121; Partners LMM ClinVar SCV000059418.5). 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). 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; PM6; PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000233499 SCV000059418 pathogenic Hypertrophic cardiomyopathy 2016-04-25 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000158511 SCV000208446 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing The G716R pathogenic variant in the MYH7 gene has been published many times in association with HCM, and it has been observed in multiple unrelated individuals tested for HCM at GeneDx (Anan et al., 1994; Hwang et al., 1998; Woo et al., 2003; Richard et al., 2003; Rai et al., 2009; Choi et al., 2010; Marsiglia et al., 2013). Anan et al. (1994) observed this pathogenic variant in three members of an Italian family; two of whom developed progressive left ventricular wall thinning and systolic dysfunction. Hwang et al. (1998) reported G716R segregated with HCM in a large, four-generation Korean family, in which multiple affected family members died of sudden cardiac death at a young age. The G716R variant has also been observed as a de novo variant in multiple individuals with HCM (Rai et al., 2009; Zhao et al., 2016). Additionally, Marsiglia et al. (2013) identified G716R in three Brazilian patients with HCM. Fujita et al. (1997) used Dictyostelium discoideum as a model to demonstrate that the G716R variant impairs motor function at the molecular level, as G716R mutants exhibited weak affinity with actin and generated a low level of force. Furthermore, the G716R variant is not observed in large population cohorts (Lek et al., 2016). The G716R 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Variants in nearby residues (D717N, R719W, R719Q, R719P) have been seen at GeneDx and reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000015161 SCV000256139 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV000233499 SCV000284259 pathogenic Hypertrophic cardiomyopathy 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 716 of the MYH7 protein (p.Gly716Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature to segregate in families with hypertrophic cardiomyopathy (HCM) (PMID: 8282798, 9874056) and has been reported in multiple unrelated individuals affected with HCM (PMID: 25935763, 12084606, 20624503, 23283745, 12707239, 12975413, 24093860, 20031618). In addition, this variant has been reported to be de novo in individuals affected with HCM (PMID: 18953637, 27161882). ClinVar contains an entry for this variant (Variation ID: 14105). One experimental study has shown that this missense change exhibited weak affinity for actin and a low level of force in an in vitro motility assay (PMID: 9062359). For these reasons, this variant has been classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000233499 SCV001245087 pathogenic Hypertrophic cardiomyopathy 2018-11-30 criteria provided, single submitter research MYH7 Gly716Arg has been previously reported in at least 15 HCM probands (Walsh R, et al., 2017; Garcia-Giustiniani D, et al., 2015; Marsiglia JD, et al., 2013; Zheng DD, et al., 2010; Rai TS, et al., 2009; Richard P, et al., 2003; Woo A, et al., 2003; Ackerman MJ, et al., 2002; Hwang TH, et al., 1998; Anan R, et al., 1994), including 2 de novo case (Zheng DD, et al., 2010; Rai TS, et al., 2009). It has also been reported to segregate in multiple affected individuals in several families (Garcia-Giustiniani D, et al., 2015; Hwang TH, et al., 1998; Choi Anan R, et al., 1994). We have identified this variant 2 probands diagnosed with HCM. In one family the variant segregated to an affected first-degree family member. The variant is very rare, being absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools PolyPhen2, CADD and MutationTaster predict this variant to be deleterious, however SIFT predicts this variant to be 'tolerated'. Functional studies suggest that the Gly716Arg variant decreases the affinity of myosin II to actin, which results in reduced force generation and subsequently compensatory hypertrophy (Fujita et al., 1997). In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Furthermore variant located in the converter region of MYH7 are predicted to result in worse outcomes (Garcia-Giustiniani D, et al., 2015). Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been reported in more than 10 unrelated probands (PS4), segregates strongly with disease (PP1_Strong), is located in a mutational hotspot (PM1), is rare in the general population (PM2) and has been reported in de novo cases (PM5) therefore we classify MYH7 Gly716Arg as 'Pathogenic'.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170502 SCV001333085 pathogenic Cardiomyopathy 2018-07-11 criteria provided, single submitter clinical testing
OMIM RCV000015161 SCV000035418 pathogenic Familial hypertrophic cardiomyopathy 1 1994-01-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158511 SCV000280310 pathogenic not provided 2012-01-16 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly716Arg in the MYH7 gene. The variant has been seen in at least 10 unrelated cases of HCM, with strong segregation data. The variant was first reported by the Seidman group in three affected first degree relatives (Anan et al 1994). Hwang et al (1998) then reported a Korean family with 5 individuals with HCM who all had the variant (two were fourth degree relatives to each other). The same group later reported longterm follow-up on that family noting that all 15 family members with HCM carried the p.Gly716Arg variant. Ackerman et al (2002) reported a patient with HCM and p.Gly716Arg who had a quite significant family history, though unfortunately no genotyping on family members was reported. This is likely the same case that was later reported in van Driest et al 2004. Richard et al (2003) observed the variant in two unrelated individuals with HCM is their French cohort. Woo et al (2003) reported two individuals with HCM and this variant in their Canadian cohort. Millat et al (2010) reported one HCM patient with p.Gly716Arg in their French cohort, which seems to be distinct from the Richard et al cohort. Rai et al (2009) reported this variant arising de novo in a proband with severe hypertrophy who died suddenly. Parental genotypes and paternity were molecularly confirmed. Parents and a brother were reported as phenotypically normal (though it is unclear if they had cardiac evaluations). Most of the reported families had a particularly high penetrance with severe disease. This variant has also been reported in one individual in our center with HCM and a strong family history of HCM and RCM with multiple family members requiring transplant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The glycine at codon 716 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon. Variants at nearby codons have been reported in association with HCM (p.Arg712Leu, p.Arg719Trp, p.Arg719Gln, p.Arg719Pro, p.Arg723Cys, p.Arg723Gly). In total the variant has not been seen in ~6,900 published controls and publicly available population datasets. There is no variation at codon 716 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 2/6/14). Please note, this does not match the patient's ancestry (Hispanic). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 2/6/14). The variant was not observed in the following published control samples: more than 100 individuals (Anan et al 1994), 100 (Richard et al 2003), 200 (van Driest et al 2004).

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