Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000251938 | SCV000320016 | uncertain significance | Cardiovascular phenotype | 2015-09-08 | criteria provided, single submitter | clinical testing | The p.R1193S variant (also known as c.3577C>A), located in coding exon 25 of the MYH7 gene, results from a C to A substitution at nucleotide position 3577. The arginine at codon 1193 is replaced by serine, an amino acid with dissimilar properties. This alteration was reported in a family with dilated cardiomyopathy (DCM) and showed incomplete penetrance (Villard E. et al. 2005 Eur Heart J 26 (794-803). An in silico model based analysis of residue p.R1193S predicted increased overall rod stiffness that may disrupt the efficacy of force generation and transmission to the extracellular matrix, which could potentially be associated with late onset DCM (Cammarato A. et al. 2011 J Mol Biol 414 (4) 477-484). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6433 samples (12866 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. |
| Invitae | RCV001854984 | SCV002186362 | pathogenic | Hypertrophic cardiomyopathy | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1193 of the MYH7 protein (p.Arg1193Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 15769782). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 264233). 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%. This variant disrupts the p.Arg1193 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22464770, 27532257; Invitae; external communication). 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. |