Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000158840 | SCV000208775 | likely pathogenic | not provided | 2018-12-18 | criteria provided, single submitter | clinical testing | The M822L likely pathogenic variant due to the nucleotide substitution c.2464 A>C in the MYH7 gene has been previously reported in one individual with HCM (Fujino et al., 2013). The same amino acid substitution due to a different nucleotide change (M822L, c.2464 A>T) has also been previously reported in another individual with HCM (Lopes et al., 2015). Furthermore, several other individuals with confirmed or suspected HCM have been reported to harbor the M822L variant; however, the nucleotide change was not specified (Mohiddin et al., 2003; Matsuta et al., 2005; Funada et al., 2010; Bayrak et al., 2015). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While M822L is a conservative amino acid substitution, it occurs at a position that is conserved across species. In addition, the majority of in silico tools also predict this variant is probably damaging to the protein structure/function. Moreover, a missense variant in the same residue (M822V) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), further supporting the functional importance of this residue of the protein. Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required. |
Invitae | RCV001207764 | SCV001379130 | uncertain significance | Hypertrophic cardiomyopathy | 2019-07-02 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine with leucine at codon 822 of the MYH7 protein (p.Met822Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency). 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). 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 disrupts the Met822 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12881443). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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"). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 23197398, 12820698). ClinVar contains an entry for this variant (Variation ID: 181370). |