ClinVar

Description

The A362D variant in the SLC26A4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A362D variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A362D 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, and in silico analysis does predict this variant is probably damaging to the protein structure/function. This substitution also occurs at a position that is conserved across species. Missense variants in nearby residues (A360V and L369E) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The A362D variant was previously interpreted to be a variant of uncertain significance. The A362D variant has been identified in trans with the T410M pathogenic variant in an affected individual at Genedx, allowing us to reinterpret A362D as a likely pathogenic variant based on the 2015 ACMG Standards and guidelines for the interpretation of sequence variants (Richards et al., 2015).