ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2464A>T (p.Met822Leu) (rs730880742)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158539 SCV000208474 likely pathogenic not provided 2017-01-06 criteria provided, single submitter clinical testing The M822L likely pathogenic variant due to the nucleotide substitution c.2464 A>T in the MYH7 gene has been previously reported in one individual with HCM (Lopes et al., 2015). The same amino acid substitution due to a different nucleotide change (M822L, c.2464 A>C) has also been previously reported in association with HCM (Fujino et al., 2013). The M822L 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 RCV000688446 SCV000816056 uncertain significance Hypertrophic cardiomyopathy 2018-04-13 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 has been reported in individuals affected with borderline or definite hypertrophic cardiomyopathy (PMID: 25351510, 19149795, 12820698). ClinVar contains an entry for this variant (Variation ID: 181188). 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). A different missense substitution at this codon (p.Met822Val) has been determined to be pathogenic (PMID: 12881443). This suggests that the methionine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be 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). 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.

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