ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2609G>T (p.Arg870Leu) (rs36211715)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000808835 SCV000948959 uncertain significance Hypertrophic cardiomyopathy 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 870 of the MYH7 protein (p.Arg870Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 25132132). ClinVar contains an entry for this variant (Variation ID: 235031). 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: 17703256, 7796500, 21674835, 19150014, 24111713, 7796500, 10725281, 23283745), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170271 SCV001332834 likely pathogenic Cardiomyopathy 2017-12-05 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223870 SCV000280331 uncertain significance not specified 2015-07-01 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. Arg870Leu (R870L; ) The Harvard Sarcomere Protein Gene Mutation Database notes that this is a novel variant first posted to the site on 8/31/2001. Per that site, the Seidman group observed this variant in two members of one family and they both had HCM. No published reports of the variant were found in Google or PubMed. Other changes at this same codon, Arg870Cys (Woo et al. 2003) and Arg870His, have been associated with HCM (Harvard Sarcomere Protein Gene Mutation Database). Variation at nearby loci of MYH7 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Ser866Tyr, Arg869Cys, Arg869Gly, Arg869His, and Met877Lys (Harvard Sarcomere Protein Gene Mutation Database). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Leucine. 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 “possibly damaging”. 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). Another change at this same codon is thought to be pathogenic: The Arg870His variant is present in dbSNP as rs36211715 (“probable-pathogenic”). It was submitted by the Dept. of Genetics at Osmania University, and also by the OMIM staff at Johns Hopkins. In total this specific Arg870Leu variant has not been seen in ~5300 individuals from publicly available population datasets. It is not present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012), in dbSNP, or in 1000 genomes (as of 1/15/2012). However, a different variation at codon 870 is listed in the NHLBI Exome Sequencing Project dataset: Arg870Cys. This was present in 1/3510 Caucasian individuals and 0/1869 African American individuals (as of 1/15/2012). It is listed in dbSNP as rs138049878, and was submitted by NHLBI-ESP.

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