ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2572C>T (p.Arg858Cys) (rs2754158)

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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 RCV000457606 SCV000199179 likely pathogenic Hypertrophic cardiomyopathy 2017-08-29 criteria provided, single submitter clinical testing The p.Arg858Cys variant in MYH7 has been reported in at least 13 heterozygous in dividuals with HCM (Ven Driest 2004, Mora 2006, Uchiyama 2009, Funada 2010, Bick 2012, Marsiglia 2013, Berge 2014, Bos 2014, Li 2015, LMM data, Chiou 2015) and de novo in 1 individual with HCM (Zhao 2017). It has also segregated with diseas e in 6 affected relatives (Chiou 2015). This variant has also been reported in C linVar (Variation ID 164324) and in 2/111684 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2754158) . This variant was predicted to be pathogenic using a computational tool clinica lly validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, although additional stu dies are required to fully establish its clinical significance, the p.Arg858Cys variant is likely pathogenic.
GeneDx RCV000225738 SCV000208471 likely pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing The R858C likely pathogenic variant in the MYH7 gene has been reported in association with cardiomyopathy and was not detected in at least 250 control individuals (van Driest et al., 2004; Mora et al., 2006; Marsiglia et al., 2013). The R858C 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 by class. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (R858H, R858P, R858S) and in nearby residues (A850D, M852T, L853Q, K865R, S866P) 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 region of the protein.In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine the clinical significance of the R858C variant, although the evidence suggests this variant is likely disease-causing.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000201448 SCV000256128 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415053 SCV000492716 likely pathogenic Muscular Diseases 2015-10-05 criteria provided, single submitter clinical testing
Invitae RCV000457606 SCV000546275 likely pathogenic Hypertrophic cardiomyopathy 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 858 of the MYH7 protein (p.Arg858Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs2754158, ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 25086479, 24111713, 24093860, 27247418, 27532257, 20975235). ClinVar contains an entry for this variant (Variation ID: 164324). A computational algorithm designed to assess the pathogenicity of missense variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be pathogenic. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this sequence change is absent from population databases but observed in several  affected individuals, and it is predicted to cause a deleterious effect on protein function. For these reasons it has been classified as Likely Pathogenic.
Phosphorus, Inc. RCV000201448 SCV000679785 likely pathogenic Familial hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000457606 SCV000886788 likely pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing

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