Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485371 | SCV000573747 | likely pathogenic | not provided | 2017-03-02 | criteria provided, single submitter | clinical testing | A S738C variant that is likely pathogenic was identified in the MYH7 gene. It has not been published as pathogenic or been reported as benign to our knowledge. Additionally, the S738C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S738C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, likely pathogenic variants at the same residue (S738R, S738T), and pathogenic/likely pathogenic missense variants in nearby residues (I736L, I736V, I736T, I736M, G741R, G741W, G741E) have been reported at GeneDx and/or reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein. |
| Invitae | RCV002526965 | SCV003263372 | uncertain significance | Hypertrophic cardiomyopathy | 2021-12-23 | criteria provided, single submitter | clinical testing | 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. 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 423978). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 738 of the MYH7 protein (p.Ser738Cys). |