ClinVar

Description

Variant summary: SLC12A3 c.363G>C (p.Glu121Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 250226 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow conclusions about variant significance. c.363G>C has been reported in the literature in individuals with Gitelman syndrome, at-least one of whom reported normal levels of urinary calcium (examples: Glaudemans_2012, and Berry 2013) and chronic kidney disease/urinary stone disease (example: Groopman_2019, Cogal_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypokalemia-Hypomagnesemia (Gitelman syndrome). At least one publication reports experimental evidence evaluating an impact on protein function in the Xenopus laevis oocyte system (example: Glaudemans_ 2012). The most pronounced variant effect results in approximately 30% of normal thiazide-sensitive NaCl cotransporter (NCC) activity and normal localization to the plasma membrane. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.