Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001228124 | SCV001400509 | likely pathogenic | Hypertrophic cardiomyopathy | 2022-03-09 | criteria provided, single submitter | clinical testing | 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. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 955476). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27532257, 27737317, 28699631, 31638223). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 877 of the MYH7 protein (p.Met877Ile). |
| Ambry Genetics | RCV002429971 | SCV002743267 | likely pathogenic | Cardiovascular phenotype | 2022-10-07 | criteria provided, single submitter | clinical testing | The p.M877I variant (also known as c.2631G>A), located in coding exon 20 of the MYH7 gene, results from a G to A substitution at nucleotide position 2631. The methionine at codon 877 is replaced by isoleucine, an amino acid with highly 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 multiple individuals with hypertrophic cardiomyopathy (HCM) (Melacini P et al. Int J Cardiol, 2008 Aug;128:364-73; Mattos BP et al. Arq Bras Cardiol, 2016 Sep;107:257-265; Walsh R et al. Genet Med, 2017 02;19:192-203; Lorenzini M et al. J Am Coll Cardiol, 2020 08;76:550-559). In addition, two other alterations located at the same position, resulting in the same protein change, c.2631G>T and c.2631G>C, have been described in individuals with HCM (De Bortoli M et al. Eur. J. Hum. Genet., 2017 10;25:1165-1169; Walsh R et al. Genet. Med., 2017 02;19:192-203; Wang B et al. Mol Med Rep, 2019 Dec;20:5229-5238). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |