Submissions for variant NM_000257.4(MYH7):c.2555T>A (p.Met852Lys)

dbSNP: rs397516157

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158847	SCV000208782	likely pathogenic	not provided	2018-05-22	criteria provided, single submitter	clinical testing	p.Met852Lys (ATG>AAG): c.2555 T>A in exon 22 of the MYH7 gene (NM_000257.2). While the M852K mutation in the MYH7 gene has not been reported to our knowledge, a mutation affecting this same residue, (M852T), has been reported in association with HCM and it was absent from more than 200 control chromosomes (Richard P et al., 2003; Gandjbakhch E et al., 2010). Additionally, mutations in nearby residues (R858P, R858C, R858G, A850D, A850T) have been reported in association with HCM, further supporting the functional importance of this residue and this region of the protein. M852K results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, M852K 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. In summary, M852K in the MYH7 gene is interpreted as a likely disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV001850226	SCV002306453	likely pathogenic	Hypertrophic cardiomyopathy	2022-11-29	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 disrupts the p.Met852 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 18403758, 24093860, 27247418). 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: 181375). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 852 of the MYH7 protein (p.Met852Lys).