Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000471791 | SCV000546191 | uncertain significance | Hypertrophic cardiomyopathy | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1248 of the MYH7 protein (p.Met1248Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32815737). ClinVar contains an entry for this variant (Variation ID: 407169). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Gene |
RCV000498303 | SCV000590148 | uncertain significance | not provided | 2017-05-31 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the MYH7 gene. The M1248K variant has not been published as pathogenic or been reported as benign to our knowledge. However, it is classified as a variant of uncertain significance in ClinVar by a different clinical laboratory in association with HCM (ClinVar SCV000546191.1; Landrum et al., 2016). The M1248K variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, M1248K is 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. Furthermore, this substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity. |