Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000227735 | SCV000284263 | uncertain significance | Hypertrophic cardiomyopathy | 2019-05-10 | criteria provided, single submitter | clinical testing | This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 824 of the MYH7 protein (p.Val824Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. 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). 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). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. |
| Ambry Genetics | RCV002444619 | SCV002735594 | uncertain significance | Cardiovascular phenotype | 2021-11-09 | criteria provided, single submitter | clinical testing | The p.V824A variant (also known as c.2471T>C), located in coding exon 20 of the MYH7 gene, results from a T to C substitution at nucleotide position 2471. The valine at codon 824 is replaced by alanine, an amino acid with similar properties. 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 alteration has been reported in hypertrophic cardiomyopathy cohorts; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203; OMGL pers. comm.). 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 alteration remains unclear. |
| Laboratory for Molecular Medicine, |
RCV000227735 | SCV000199190 | likely pathogenic | Hypertrophic cardiomyopathy | 2015-02-10 | no assertion criteria provided | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |