ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000243586 SCV000320678 likely pathogenic Cardiovascular phenotype 2016-01-05 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000158521 SCV000208456 pathogenic not provided 2018-10-09 criteria provided, single submitter clinical testing The G741R pathogenic variant due to the nucleotide substitution c.2221 G>A in the MYH7 gene has been previously reported in multiple individuals with HCM (Fananapazir et al., 1993; Richard et al., 2013). Fananapazir et al. (1993) also reported the same amino acid substitution due to a different nucleotide change (G741R, c.2221 G>C) in another family with HCM. The G741R variant has been reported in several other individuals with HCM; however, the nucleotide change was not specified (Malinchik et al., 1997; Van Driest et al., 2004; Kaski et al., 2009; Theis et al., 2009; Kindel et al., 2012; Marsiglia et al., 2013). The G741R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, multiple pathogenic missense variants at this residue (G741W, G741A) have been reported in HGMD in association with HCM (Stenson et al., 2014), further supporting the functional importance of this residue of the protein.
Invitae RCV000461730 SCV000546276 pathogenic Hypertrophic cardiomyopathy 2018-04-06 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). There are two reported DNA changes (c.2221G>A amd c.2221G>C) that lead to this amino acid change (p.Gly741Arg) and they have been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 12707239, 8483915, 25935763, 20800588). ClinVar contains an entry for this variant (Variation ID: 42890). A different missense substitution at this codon (p.Gly741Trp) has been determined to be pathogenic and found in individuals affected with hypertrophic cardiomyopathy (PMID: 8533830, 15856146, 22112859, 26914223). This suggests that the glycine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. 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, but these predictions have not been confirmed by published functional studies. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000461730 SCV000059429 likely pathogenic Hypertrophic cardiomyopathy 2014-04-22 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158521 SCV000280318 pathogenic not provided 2014-07-15 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.Gly741Arg in the MYH7 gene. This variant has been seen in at least 9 cases of HCM. Fananapazir (1993) reported the variant in two unrelated families with HCM; the variant co-segregated with HCM in three affected members of one family and two affected members of the other family. Song et al (2005) observed the variant arising de novo in an individual with HCM. Richard et al (2003) reported the variant in one individual with HCM. Millat et al (2010) reported the identification of this variant in a cohort of individuals studied using high resolution melting to identify variants (this case may be redundant with the Richards et al case as both came from French cohorts). Keller et al (2005) reported the variant in a woman with HCM in their Swiss cohort. Kaski et al (2009) observed the variant in two unrelated children with HCM in a British cohort. We have also observed this variant in another patient with HCM in our clinic. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation Taster predicts this to be disease causing. The glycine at codon 741 is conserved across species, as are neighboring amino acids. Two other variants at the same codon have been associated with cardiomyopathy: p.Gly741Ala (primary data unavailable), p.Gly741Trp (we consider this variant likely disease causing). Variants at nearby codons have also been reported in association with cardiomyopathy (p.Ile736Val, p.Ile736Thr, p.Ile736Met, p.Ala742Glu, p.Glu743Asp). Functional studies have shown that p.Gly741Arg confers reduced isometric force generation and decreased velocity of shortening (Lankford et al 1995). In total the variant has not been seen in ~6,720 published controls and publicly available population datasets. There is no variation at codon 741 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/20/13). There is also no variation at codon 741 listed in dbSNP or 1000 genomes (as of 9/20/13). The variant was not observed in the following published control samples: 120 general population individuals studied by Song et al (2005) (likely Chinese ancestry), 100 healthy adults reported by Richard et al (2003). No further control data was provided by GeneDx or the other authors cited above.

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