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

dbSNP: rs1060505018

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000695003	SCV000823477	pathogenic	Hypertrophic cardiomyopathy	2023-01-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met877 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 573352). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27737317, 28699631, 32731933). 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).
Color Diagnostics, LLC DBA Color Health	RCV001191955	SCV001359897	uncertain significance	Cardiomyopathy	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 877 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32731933; communication with an external laboratory; ClinVar SCV000823477.5). Different variants affecting the same codon and causing the same amino acid change, c.2631G>T and c.2631G>A, have been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 17643520, 20513729, 27532257, 27737317, 28699631, 30297972; communication with an external laboratory; ClinVar SCV001576910.2, SCV001400509.3), suggesting that methionine at this position is important for the protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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.
Genetics and Molecular Pathology, SA Pathology	RCV003447556	SCV004175349	likely pathogenic	Hypertrophic cardiomyopathy 1	2021-10-27	criteria provided, single submitter	clinical testing	The MYH7 c.2631G>C variant is a single nucleotide change in exon 22/40 of the MYH7 gene, which is predicted to change the amino acid methionine at position 877 in the protein, to isoleucine. This variant is located in the conserved MYH7 functional domain (within amino acids 181-937) (PM1) and has been reported in at least 6 probands with a clinical presentation of Hypertrophic cardiomyopathy (PMID#32731933, 28699631, 27737317, SA Pathology cohort) (PS4_Moderate). It is reported to co-segregate with disease in 4 meioses in 3 families; PMID#27737317, 28699631, SA Pathology cohort (PP1). This variant is absent from population databases (PM2), is reported in dbSNP (rs1060505018), is reported as ?disease causing in HGMD (CM1616701) and has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 573352). Other changes at this same amino acid (p.M877K/T) are also reported as disease causing in individuals with hypertrophic cardiomyopathy, further strengthening the likely importance of this amino acid in the MYH7 protein.