Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000254190 | SCV000320540 | likely pathogenic | Cardiovascular phenotype | 2022-03-25 | criteria provided, single submitter | clinical testing | The p.S782N variant (also known as c.2345G>A), located in coding exon 19 of the MYH7 gene, results from a G to A substitution at nucleotide position 2345. The serine at codon 782 is replaced by asparagine, an amino acid with highly similar properties. This variant has been previously reported in individuals reported to have hypertrophic cardiomyopathy (HCM) (Rayment et al. Proc Natl Acad Sci USA. 1995;92(9):3864-8; Mohiddin et al. Genet Test. 2003;7(1):21-7; Witjas-Paalberends et al. Cardiovasc Res. 2013;99(3):432-41). 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). In addition, other alterations affecting this amino acid (p.S782D (c.2344_2345delinsGA), p.S782R (c.2346C>A), and p.S782R (c.2346C>G)) have also been reported in association with HCM (Moric et al. J Appl Genet. 2003;44(1):103-9; Olivotto et al. Mayo Clin Proc. 2008;83(6):630-8; Zou et al. Mol Biol Rep. 2013;40(6):3969-76). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV000477389 | SCV000546186 | pathogenic | Hypertrophic cardiomyopathy | 2023-08-04 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 782 of the MYH7 protein (p.Ser782Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12820698, 23674513). ClinVar contains an entry for this variant (Variation ID: 264539). 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. This variant disrupts the p.Ser782 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18533079, 23283745, 26914223, 27247418). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |