Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000493512 | SCV000581725 | likely pathogenic | not provided | 2017-05-03 | criteria provided, single submitter | clinical testing | The Y376H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y376H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant 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. This substitution occurs at a position that is conserved across species, and a different missense variant at the same position (Y376N) has been previously reported as a de novo variant in an individual with limb-girdle muscular dystrophy (Menezes et al., 2012). Additionally, missense variants in nearby residues (M371K; R377C/H/L; L379F; L380S) have been reported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. |