Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000698524 | SCV000827192 | uncertain significance | Hypertrophic cardiomyopathy | 2024-02-13 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 913 of the MYH7 protein (p.Ile913Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 576107). 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 with a positive predictive value of 95%. 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. |
| Ambry Genetics | RCV004026447 | SCV005033846 | likely pathogenic | Cardiovascular phenotype | 2024-01-12 | criteria provided, single submitter | clinical testing | The p.I913S variant (also known as c.2738T>G), located in coding exon 21 of the MYH7 gene, results from a T to G substitution at nucleotide position 2738. The isoleucine at codon 913 is replaced by serine, an amino acid with dissimilar properties. Another alteration at the same codon, p.I913T (c.2738T>C), has been detected in hypertrophic cardiomyopathy (HCM) cohorts (Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7; Walsh R et al. Genet Med, 2017 Feb;19:192-203). 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 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. |