ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2608C>T (p.Arg870Cys) (rs138049878)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148707 SCV000190437 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000758035 SCV000564433 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2608C>T (p.Arg870Cys) variant in MYH7 has been reported in 5 individuals with hypertrophic cardiomyopathy (PS4_Supporting; PMID:10862102; PMID:12975413; PMID:24621997; Partners LMM ClinVar SCV000203913). This variant segregated with disease in 1 affected individual (insufficient to meet PP1 criteria; Partners LMM ClinVar SCV000203913). This variant has been identified in 1/66728 European chromosomes (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2609G>A p.Arg870His; ClinVar Variation ID 14120). 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): PM1; PM2; PM5; PP3; PS4_ Supporting
GeneDx RCV000158554 SCV000208489 likely pathogenic not provided 2018-08-28 criteria provided, single submitter clinical testing The R870C likely pathogenic variant in the MYH7 gene has previously been published in association with HCM (Anan et al., 2002; Woo et al., 2003; Funada et al., 2010; Otsuka et al., 2012; Fujita et al., 2013; Alfares et al., 2015; Hayashi et al., 2018). Otsuka et al. (2012) identified the R870C variant in two siblings with HCM whose mother died of sudden cardiac death. Anan et al. (2002) identified this variant in an individual with HCM and five family members. However, assessment of segregation in this family is limited as it is unclear whether these relatives were also affected (Anan et al., 2002). This variant has also been observed in multiple other unrelated individuals referred for HCM genetic testing at GeneDx, and has been classified as likely pathogenic by the ClinGen Inherited Cardiomyopathy Expert Panel (ClinVar SCV000564433.2; Landrum et al., 2016). The R870C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). R870C results in 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, a different pathogenic missense variant affecting the same codon (R870H) has been reported in association with HCM and was observed to segregate with disease (Bashyam et al., 2007; Garcia-Castro et al., 2009; Coto et al., 2012; Zou et al., 2013), further supporting the functional significance of this residue.
Invitae RCV000758035 SCV000957373 likely pathogenic Hypertrophic cardiomyopathy 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 870 of the MYH7 protein (p.Arg870Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs138049878, ExAC 0.001%). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 30022097, 12975413, 25132132, 10862102, 27532257, 20975235, 22112859, 28771489). ClinVar contains an entry for this variant (Variation ID: 161326). 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 and their clinical significance is uncertain. This variant disrupts the p.Arg870 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 12974739, 17703256, 7796500, 9172070, 17192269, 21674835, 19150014, 24111713), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000758035 SCV000203913 likely pathogenic Hypertrophic cardiomyopathy 2017-02-20 criteria provided, single submitter clinical testing The p.Arg870Cys variant in MYH7 has been reported in 7 individuals with HCM (5 i ndividuals: Anan 2000, Woo 2003, Otsuka 2012, Fujita 2013, Homburger 2016 and 2 individuals: LMM unpublished) and segregated with disease in 2 affected relative s from 2 families (Otsuka 2012 and LMM). This variant has been identified in 1/6 6728 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs138049878). Computational prediction tools and cons ervation analysis suggest that the p.Arg870Cys variant may impact the protein an d another variant at the same codon (p.Arg870His) is classified as pathogenic va riant by our laboratory. In addition, this variant is located in the head domai n of the MYH7 protein, where studies have shown an increased probability for bei ng pathogenic (Walsh 2016). In summary, the p.Arg870Cys variant is likely pathog enic for HCM.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158554 SCV000280329 likely pathogenic not provided 2014-12-23 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. Arg870Cys has been previously observed in association with hypertrophic cardiomyopathy (HCM) in at least 5 unrelated individuals, apparently with good segregation data in one family. Anan et al. (2000) found Arg870Cys in a 61-year-old man of Japanese descent with asymmetrical septal hypertrophy. It appears to have segregated with disease in 5 of his affected family members, but the language of the report is vague (“5 individuals in this family were affected with the mutation.”) The Seidman’s Harvard Sarcomere Protein Gene Mutation Database reports the variant in a male HCM patient with onset at age 13. Woo et al. (2003) found the variant in a Toronto proband with HCM and a family history of 4 other affecteds including 3 premature sudden deaths under the age of 60. Average age at diagnosis for this family was 45 years. No segregation data in affected family members was provided, although several unaffecteds were tested. Arg870Cys has also been observed in two other unrelated individuals tested for HCM at GeneDx, according to the report. Variation at this same locus has been associated with disease, most notably Arg870His which we categorize as very likely diseae causing. The Arg870His variant has been reported in at least 11 unrelated cases of HCM with strong segregation data in one SE-Asian Indian family (11 individuals), good segregation data in 2 additional families, and weak segregation data in two more. Structural and functional data are available. In total it had not been seen in ~5670 published controls and publicly available population datasets as of 1/15/2012. It is present in dbSNP as rs36211715 (“probable-pathogenic”), submitted by the Dept. of Genetics at Osmania University, and also by the OMIM staff at Johns Hopkins. Another variant at this site, Arg870Leu, was reported by the Harvard Sarcomere Protein Gene Mutation Database as a novel variant observed by the Seidman group in two members of one family who both had HCM. Variation at nearby codons of MYH7 (within 10 amino acids to either side) has also been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Ser866Tyr, Ala868Pro, Arg869Cys, Arg869Gly, Arg869His, and Met877Lys (Harvard Sarcomere Protein Gene Mutation Database; Human Gene Mutation Database as reported by GeneDx). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a neutral, polar Cysteine. The Arginine at codon 870 is highly conserved across 40 vertebrate species examined (it is a lysine in 2 species: Stickleback and Tetraodon). Surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” and SIFT predicts it to be “deleterious”. This variant is in the rod domain of the beta-myosin heavy chain protein (Rayment et al. 1995) localized to the coiled-coil alpha-helical S-2 region (Cuda et al. 1997). In total the Arg870Cys variant been seen in 1 out of ~6850 individuals from published controls and publicly available population datasets. It is present in 1/4300 Caucasian individuals and 0/2200 African American individuals in the NHLBI Exome Sequencing Project dataset (as of 11/16/2012). It is listed in dbSNP as rs138049878, and was submitted by NHLBI-ESP. It is not present in 1000 genomes (as of 11/16/2012). Anan et al. (2000) did not find it in at least 50 control individuals of unspecified ancestry, who were likely Japanese to match the affecteds. Woo et al. (2003) did not find it in 106 control individuals. It was not present in up to 200 control individuals of Caucasian and African-American ancestry tested at GeneDx.

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