Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000473139 | SCV000546177 | uncertain significance | Hypertrophic cardiomyopathy | 2017-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine with cysteine at codon 718 of the MYH7 protein (p.Phe718Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MYH7-related disease. A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. |
| Gene |
RCV000486340 | SCV000565286 | likely pathogenic | not provided | 2018-12-19 | criteria provided, single submitter | clinical testing | A novel F718C variant that is likely pathogenic was identified in the MYH7 gene. It has not been published as pathogenic or been reported as a benign polymorphism to our knowledge. The F718C variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. Located in the myosin motor domain of MYH7, the F718C 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 highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G716A, G716R, R719Q, R719P, R719W) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000486340 | SCV000924877 | uncertain significance | not provided | 2016-09-02 | no assertion criteria provided | provider interpretation |