ClinVar Miner

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

dbSNP: rs730880757
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Total submissions: 4
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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;, 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

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