ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys) (rs45611033)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658686 SCV000780471 likely pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000628877 SCV000564441 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.3133C>T (p.Arg1045Cys) variant in MYH7 has been reported in 11 individuals with hypertrophic cardiomyopathy (PS4; PMID:24510615; PMID:18533079; PMID:27532257; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000204029.4). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM2; PP3
GeneDx RCV000658686 SCV000208522 likely pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing The R1045C likely pathogenic variant in the MYH7 gene has been reported multiple times in association with HCM (Olivotto et al., 2008; Bos et al., 2014; Kapplinger et al., 2014; Cecconi et al., 2016; Homburger et al., 2016; Rubattu et al., 2016; Michels et al., 2017). This variant has also been reported in association with DCM, yet the affected patient(s) also harbored a de novo variant in the TNNC1 gene (Pinto et al., 2011; Rampersaud et al., 2011). R1045C has been identified independently in multiple probands with HCM referred for cardiomyopathy genetic testing at GeneDx, and has segregated with disease in at least three relatives from two different families. R1045C is not observed at a significant frequency (0.0025% global alleles) in large population cohorts (Lek et al., 2016). The R1045C 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. Moreover, in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Finally, two missense variants in the same residue (R1045L, R1045H) have been reported in the Human Genome Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this residue.
Invitae RCV000628877 SCV000749785 pathogenic Hypertrophic cardiomyopathy 2018-05-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1045 of the MYH7 protein (p.Arg1045Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs45611033, ExAC 0.01%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 27247418, 27483260, 27532257, 27600940). It has also been found to co-occur with a de novo variant in TNNC1 gene in an individual affected with dilated cardiomyopathy (PMID: 21832052). ClinVar contains an entry for this variant (Variation ID: 177753). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Two additional missense substitutions at this codon (p.Arg1045Leu, p.Arg1045His) have been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 26199943, 27247418, 27532257). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000628877 SCV000204029 likely pathogenic Hypertrophic cardiomyopathy 2019-03-08 criteria provided, single submitter clinical testing The p.Arg1045Cys variant in MYH7 has been reported in at least 14 individuals wi th hypertrophic cardiomyopathy, one of whom carried a second disease causing var iant in another gene, and 1 individual with infantile DCM, who carried a second possible disease-causing variant in another gene (Olivotto 2008, Hershberger 200 8, Rampersaud 2011, Kapplinger 2014, Cecconi 2016, Homburger 2016, Rubattu 2016, Walsh 2017, Michels 2017, LMM data). It has also been identified in 1/10368 Ash kenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This var iant was classified as Likely Pathogenic on December 15, 2016 by the FDA-approve d ClinGen Inherited Cardiomyopathy Expert Panel (Submission ID SCV000564441.3). Computational prediction tools and conservation analysis suggest that this varia nt may impact the protein, though this information is not predictive enough to d etermine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be cla ssified as likely pathogenic for autosomal dominant hypertrophic cardiomyopathy. ACMG/AMP Criteria applied: PS4, PM2, PP3.

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