Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Agnes Ginges Centre for Molecular Cardiology, |
RCV000172883 | SCV000223873 | uncertain significance | Hypertrophic cardiomyopathy 1 | 2016-12-17 | criteria provided, single submitter | research | This MYH7 Met493Lys variant has not been previously described. However, genetic screening of HCM cohorts have reported variants at the same position which result in different amino acid substitutions (Met493Leu, Met493Ile and Met493Val) suggesting that an amino acid substitution at this site may not be tolerated. MYH7 Met493Lys is absent from the 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). In a large HCM population study Walsh et al., identified that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. We have identified the MYH7 Met493Lys variant in 1 HCM proband. Methionine at position 493 is highly conserved across distantly related species, and computational tools SIFT, MutationTaster and Polyphen_HCM predict the variant to be deleterious. Based on the absence of this variant in the general population, predictions from a number of in silico models, and because the variant is located in a 'hotspot' of MYH7, we classify Met493Lys as a variant of 'uncertain significance'. |