Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000158518 | SCV000208453 | likely pathogenic | not provided | 2017-10-18 | criteria provided, single submitter | clinical testing | p.Gly733Val (GGA>GTA): c.2198 G>T in exon 20 of the MYH7 gene (NM_000257.2). The Gly733Val variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Gly733Val results in a conservative amino acid substitution of one non-polar amino acid with another, this substitution occurs at a position that is highly conserved across species. In silico analysis predicts Gly733Val is probably damaging to the protein structure/function. Mutations at the same residue (Gly733Arg, Gly733Glu) and in nearby residues (Pro731Leu, Gln734Pro, Gln734Glu) have been reported in association with cardiomyopathy, further supporting the functional importance of this residue and this region of the protein. Furthermore, Gly733Val was not present in the 1000 Genomes database, and the NHLBI ESP Exome Variant Server reports Gly733Val was not observed in approximately 6500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, Gly733Val is a good candidate for a disease-causing mutation. The variant is found in HCM panel(s). |
| Invitae | RCV003586154 | SCV004296278 | likely pathogenic | Hypertrophic cardiomyopathy | 2023-12-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 733 of the MYH7 protein (p.Gly733Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24111713, 28193612; Invitae). ClinVar contains an entry for this variant (Variation ID: 181177). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |