ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

ACMG criteria used:PM1 PM2 BS2, BP2

BP4, PM3

Variant summary: SLC12A3 c.965C>T (p.Ala322Val) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251454 control chromosomes in the gnomAD database, including 6 homozygotes. c.965C>T has been reported in the literature in individuals affected with Familial Hypokalemia-Hypomagnesemia (Vargas-Poussou_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypokalemia-Hypomagnesemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21415153). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Reported along with a second variant in the SLC12A3 gene in two patients with Gitelman syndrome in the published literature; however, segregation information was not provided (PMID: 21415153); Reported as a variant of uncertain clinical significance along with two additional SLC12A3 variants in an individual referred from a nephrology clinic; however specific phenotype and segregation information was not provided (PMID: 33226606); Reported as a single heterozygous variant in an individual with salt-wasting congenital adrenal hyperplasia with subsequent hypokalemia; a homozygous pathogenic variant in CYP21A was also identified (PMID: 33763274); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 33226606, 21415153, 33763274)

SLC12A3: BP4, BS2

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).