ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2080C>T (p.Arg694Cys) (rs727504240)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000158506 SCV000203858 uncertain significance not specified 2017-04-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg694Cys variant in MYH7 has been reported in at least 11 individuals with HCM, and segr egated with disease in 3 affected relatives from 2 families (Andersen 1999, Van Driest 2004, Witjas-Paalberends 2013, Alfares 2015, pers comm) and has also been reported in ClinVar (Variant ID: 177627). However, at least 4 individuals, incl uding the individual reported by Van Driest, also carried an additional likely d isease causing variant in the MYBPC3 gene (Van Driest 2004, pers comm). In addit ion, this variant has also been identified in 2/66398 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s727504240). Arginine (Arg) at position 694 is highly conserved in mammals and across evolutionarily distant species and the change to cysteine (Cys) was predi cted to be pathogenic using a computational tool clinically validated by our lab oratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Of note, this variant lies in the head region of the protei n. Missense variants in this region have been reported and statistically indicat ed to be more likely to cause disease (Walsh 2016). In summary, while there is s ome suspicion for a pathogenic role, the clinical significance of the p.Arg694Cy s variant is uncertain.
GeneDx RCV000158506 SCV000208441 uncertain significance not specified 2017-03-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The R694C variant has been published in association with HCM; however, these patients also harbored reportedly pathogenic variants in other HCM-related genes (Andersen et al., 1999; Van Driest et al., 2004; Olivotto et al., 2008). Additionally, while missense variants in the same residue (R694L, R694H) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Nevertheless, the R694C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Ambry Genetics RCV000618360 SCV000740227 uncertain significance Cardiovascular phenotype 2017-10-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000628970 SCV000749880 likely pathogenic Hypertrophic cardiomyopathy 2018-05-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 694 of the MYH7 protein (p.Arg694Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs727504240, ExAC 0.003%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 22811549, 27247418, 27532257, 23197161) including a family that also carried a variant of uncertain significance in MYBPC3 (PMID: 10563488, 12566107). ClinVar contains an entry for this variant (Variation ID: 177627). 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). The observation of one or more missense substitutions at this codon (p.Arg694Leu and p.Arg694His) in affected individuals suggests that this may be a clinically significant residue (PMID: 20819418, 12974739). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000663405 SCV000786691 uncertain significance Myopathy, distal, 1 criteria provided, single submitter research The heterozygous p.Arg694Cys variant in MYH7 has been identified by our project in one individual with distal myopathy. This variant has been reported in at least 11 individuals with HCM, and was found to segregate with disease in 3 affected relatives across 2 families (Andersen 1999, Van Driest 2004, Witjas-Paalberends 2013, Alfares 2015, pers comm). However, at least 4 of those individuals, including the individual reported by Van Driest, also carried an additional likely disease causing variant in the MYBPC3 gene (Van Driest 2004, pers comm). Additionally, this variant has been reported in ClinVar by two seperate clinical laboratories that both currently classify it as a Variant of Uncertain Significance (LMM pers comm, Variant ID: 177627). Other missense variants at the same residue (Arg694Leu, Arg694His) have been reported in the Human Gene Mutation Database in association with cardiomyopathy, however they are both of uncertain significance (Stenson et al., 2014). This variant has been identified in 0.01% (1/17,248) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504240). In summary, the clinical significance of the p.Arg694Cys variant is uncertain.
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000786922 SCV000925823 likely pathogenic Familial hypertrophic cardiomyopathy 1 2018-12-12 no assertion criteria provided clinical testing

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