ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2631G>C (p.Met877Ile) (rs1060505018)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000695003 SCV000823477 likely pathogenic Hypertrophic cardiomyopathy 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 877 of the MYH7 protein (p.Met877Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28699631, 27737317). It has also been observed to segregate with disease in related individuals. 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 disrupts the p.Met877 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133230, 22429680). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Health, Inc RCV001191955 SCV001359897 uncertain significance Cardiomyopathy 2019-06-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001191955 SCV001467922 likely pathogenic Cardiomyopathy 2020-12-29 criteria provided, single submitter clinical testing Variant summary: MYH7 c.2631G>C (p.Met877Ile) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251406 control chromosomes (gnomAD). c.2631G>C has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Walsh_2016). In addition, the p.Met877Ile variant (nucleotide change not specified) has been reported in families affected with cardiomyopathy (Mattos_2016, Wang_2019), and was indicated to segregate with disease (Mattos_2016). Other variants in this position that result in the same p.Met877Ile amino acid change have also been reported in individuals with cardiomyopathy (c.2631G>A, e.g. Walsh_2016; c.2631G>T, e.g. Bortoli_2017), providing further evidence that this change may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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