ClinVar

Description

A variant of uncertain significance has been identified in the CLCN1 gene. The A218T variant has been reported in the heterozygous state in an individual with Thomsen disease; however, it did not segregate with Thomsen disease in the affected father and functional characterization of the variant was not performed (de Diego et al., 1999). The A218T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations, and it was not observed with any significant frequency in the 1000 Genomes Project. The A218T 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 where amino acids with similar properties to Alanine are tolerated across species. Additionally, a missense variant in a nearby residue (V217D) has been reported in the Human Gene Mutation Database in association with a CLCN1-related disorder (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.