ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2711G>A (p.Arg904His) (rs397516165)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000208309 SCV000059467 likely pathogenic Primary dilated cardiomyopathy 2018-03-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000505767 SCV000208502 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The R904H variant in the MYH7 gene has been reported multiple times in association with MYH7-related cardiac disorders (Waldmuller et al., 2011; Chami et al., 2014). Additionally, this variant has been seen in several individuals with cardiomyopathy who have undergone testing at GeneDx. The R904H variant 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. Although R904H is a conservative amino acid change, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant in the same residue (R904C) and variants in nearby residues (E903K, E903Q, E903G, C905R, C905F, C905Y) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. We interpret the maternally inherited R904H variant as a pathogenic variant.
Blueprint Genetics RCV000208309 SCV000264084 likely pathogenic Primary dilated cardiomyopathy 2015-03-17 criteria provided, single submitter clinical testing
Invitae RCV000550238 SCV000623680 pathogenic Hypertrophic cardiomyopathy 2018-04-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 904 of the MYH7 protein (p.Arg904His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (PMID: 21750094, 25448463, 27532257), including in one DCM individuals with DCM where the variant arised de novo (PMID: 22464770, Invitae). ClinVar contains an entry for this variant (Variation ID: 42926). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000620255 SCV000737379 likely pathogenic Cardiovascular phenotype 2016-12-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769455 SCV000900849 likely pathogenic Cardiomyopathy 2016-11-09 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845382 SCV000987441 pathogenic Familial dilated cardiomyopathy criteria provided, single submitter clinical testing

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