Submissions for variant NM_000257.4(MYH7):c.2714G>C (p.Cys905Ser)

dbSNP: rs730880757

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000628883	SCV001976464	uncertain significance	Hypertrophic cardiomyopathy	2021-09-22	reviewed by expert panel	curation	The NM_000257.4: c.2714G>C (p.Cys905Ser) variant in MYH7 has been reported in 1 individual with HCM (GeneDx pers. comm.); however this data is insufficient to apply the PS4 criterion. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PM1, PP3.
GeneDx	RCV000158568	SCV000208503	pathogenic	not provided	2012-07-13	criteria provided, single submitter	clinical testing	p.Cys905Ser (TGT>TCT): c.2714 G>C in exon 23 of the MYH7 gene (NM_000257.2). The Cys905Ser mutation in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. However, a mutation affecting this same codon, Cys905Phe, has been reported in association with HCM (Erdmann J et al., 2003). Mutations in nearby residues (Glu903Gly, Glu903Lys, Arg904Cys, Arg904His, Asp806Gly) have been reported in association with cardiomyopathy, further supporting the functional importance of this codon and this region of the protein. Cys905Ser results in a semi-conservative amino acid substitution which leads to a loss of a Cysteine, which may impact disulfide bond formation in the MYH7 protein. Furthermore, the NHLBI ESP Exome Variant Server reports Cys905Ser was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, Cys905Ser in the MYH7 gene is interpreted as a likely disease-causing mutation. The variant is found in HCM panel(s).
Invitae	RCV000628883	SCV000749791	likely pathogenic	Hypertrophic cardiomyopathy	2022-11-29	criteria provided, single submitter	clinical testing	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. 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.Cys905 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 12974739, 22859017, 25132132), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 181203). 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 cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 905 of the MYH7 protein (p.Cys905Ser).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769454	SCV000900848	uncertain significance	Cardiomyopathy	2016-12-06	criteria provided, single submitter	clinical testing