ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2156G>C (p.Arg719Pro) (rs121913641)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201464 SCV000256126 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV001209616 SCV001381060 likely pathogenic Hypertrophic cardiomyopathy 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 719 of the MYH7 protein (p.Arg719Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of hypertrophic cardiomyopathy (PMID: 25935763). ClinVar contains an entry for this variant (Variation ID: 217460). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant disrupts the p.Arg719 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7848441, 23140321). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223766 SCV000280313 uncertain significance not specified 2015-06-10 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. Arg719Pro (R719P; G>C at nucleotide level) Other changes at this same codon, Arg719Trp and Arg719Gln, 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 Arg712Leu, Gly716Arg, Arg723Cys, Arg723Gly, and Ala728Val (Harvard Sarcomere Protein Gene Mutation Database). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Proline. The Arginine at codon 719 is highly conserved across 41 vertebrate species examined (it is a Lysine in 7 species: Chicken, Tetraodon, Fugu, Stickleback, Medaka, Zebrafish, and Lamprey). Surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 ( predicts the variant to be “possibly damaging”. In total the variant has not been seen in ~5300 individuals from publicly available population datasets. There is no variation at codon 719 listed 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). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012).

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