Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory of Genetics and Molecular Cardiology, |
RCV000201487 | SCV000256144 | likely pathogenic | Hypertrophic cardiomyopathy 1 | criteria provided, single submitter | clinical testing | ||
| Invitae | RCV001853227 | SCV002299405 | pathogenic | Hypertrophic cardiomyopathy | 2023-08-10 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Ile702 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25611685, 33336002; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 217470). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23283745, 24093860, 27247418, 27532257, 30847666). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 702 of the MYH7 protein (p.Ile702Val). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002415859 | SCV002725908 | likely pathogenic | Cardiovascular phenotype | 2021-06-24 | criteria provided, single submitter | clinical testing | The p.I702V variant (also known as c.2104A>G), located in coding exon 17 of the MYH7 gene, results from an A to G substitution at nucleotide position 2104. The isoleucine at codon 702 is replaced by valine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been detected in several apparently unrelated individuals reported to have hypertrophic cardiomyopathy (HCM) or who underwent genetic testing for suspicion of HCM (Marsiglia JD et al. Am Heart J, 2013 Oct;166:775-82; Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; Oliveira TG et al. J Mol Diagn, 2015 Jul;17:420-30; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Mazzarotto F et al. Genet Med, 2019 02;21:284-292; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |