ClinVar

Description

Variant summary: CLCNKB c.1313G>A (p.Arg438His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251002 control chromosomes. c.1313G>A has been reported in the literature in multiple individuals affected with Bartter Syndrome, Type 3, including homozygotes with with evidence of familial co-segregation who show phenotypic features of both Gitelman and classic Bartter syndrome (example: Zelikovic_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Keck_2013). The most pronounced variant effect results in absent electric current capability and a severely reduced protein product. The following publications have been ascertained in the context of this evaluation (PMID: 23703872, 12472765). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.