ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2221G>C (p.Gly741Arg) (rs121913632)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621362 SCV000740146 likely pathogenic Cardiovascular phenotype 2018-03-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000472342 SCV000564427 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2221G>C (p.Gly741Arg) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:8483915; PMID:15563892; PMID:20031618; PMID:15358028; Partners LMM ClinVar SCV000059430.5; SHaRe consortium, PMID: 30297972). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:15563892). This variant segregated with disease in 3 affected individuals (PP1; PMID:8483915; Partners LMM ClinVar SCV000059430.5). 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). 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.2221G>T p.Gly741Trp - Variation ID 177665). 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; PM1; PM2; PM5; PM6; PP1; PP3
GeneDx RCV000158522 SCV000208457 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing p.Gly741Arg (GGG>CGG): c.2221 G>C in exon 20 of the MYH7 gene (NM_000257.2). The G741R mutation in the MYH7 gene was first reported in three individuals with HCM from one family Fananapazir L et al., 1993). The same study reported the same amino acid substitution but due to a different nucleotide change (G741R, c.2221 G>C) in another family with HCM. G741R was later published as being present in one individual with HCM and absent from 200 control chromosomes (Richard P et al., 2003). In addition, G741R was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations at the same residue (G741W, G741A) and in nearby residues (I736T, A742E, E743D) have been published in association with HCM, supporting the functional significance of this residue and this region of the protein. G741R is a non-conservative amino acid substitution, meaning this change 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 that is highly conserved across species. In summary, G741R in the MYH7 gene is interpreted to be a disease-causing mutation. The variant is found in HCM,DCM-CRDM panel(s).
Invitae RCV000472342 SCV000546223 pathogenic Hypertrophic cardiomyopathy 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 741 of the MYH7 protein (p.Gly741Arg). 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 individuals affected with hypertrophic cardiomyopathy and has been shown to segregate with the disease in one HCM family (PMID: 15563892, 8483915). ClinVar contains an entry for this variant (Variation ID: 14098). A different variant (c.2221G>A) giving rise to the same protein effect observed here (p.Gly741Arg) has been reported in individuals and families affected with HCM (PMID: 8483915, 12707239, 24111713). Other individuals have also been described to carry p.Gly741Arg, but the exact nucleotide change associated has not been reported (PMID: 15358028, 20031618, 24093860, 24704860). A different missense substitution at this codon (p.Gly741Trp) is reported to be deleterious (PMID: 15856146, 8533830). This indicates that this residue is critical for protein function. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Furthermore, experimental studies using skinned slow skeletal muscle fibers carrying p.Gly741Arg have shown that this variant may decrease the maximum shortening of velocity and the isometric force generation (PMID: 7883988). However, the clinical significance of these findings is unknown. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000472342 SCV000059430 likely pathogenic Hypertrophic cardiomyopathy 2015-10-16 criteria provided, single submitter clinical testing The p.Gly741Arg variant has been reported in >10 individuals with HCM, occurred de novo in one of them, and segregated with disease in 3 affected relatives from 2 families (Fananapazir 1993, Malinchik 1997, Richard 2003, Van Driest 2004, So ng 2005, Kaski 2009, LMM unpublished data). It has not been identified in large population studies. This variant was predicted to be pathogenic using a computat ional tool clinically validated by our laboratory. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). In summary, altho ugh additional studies are required to fully establish its clinical significance , this variant is likely pathogenic.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000015154 SCV000256140 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
OMIM RCV000015154 SCV000035411 pathogenic Familial hypertrophic cardiomyopathy 1 1993-05-01 no assertion criteria provided literature only

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