ClinVar Genomic variation as it relates to human health

Across a selection of the available literature, the SLC12A3 c.2581C>T (p.Arg861Cys) variant has been reported in at least seven studies and is found in at least 20 patients with Gitelman syndrome including one in a homozygous state and 19 in a compound heterozygous state, with one sibling pair who also carried a null variant on the second allele (Lemmink et al. 1998; Ji et al. 2008; Favre et al. 2012; Berry et al. 2013; Jiang et al. 2015; Grillone et al. 2016; Valdez-Flores et al. 2016). Patients had a range of phenotypes consistent with Gitelman syndrome including absence of arterial hypertension, hypokalemia of renal origin, hypomagnesia, hypocalciuria, and paresthesia after exercise (Favre et al. 2012; Grillone et al. 2016). The p.Arg861Cys variant was absent from 50 control chromosomes and is reported at a frequency of 0.000185 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Arg861Cys variant demonstrated reduced NaCl cotransporter activity, lower phosphorylation ability, and reduced cell surface presence compared to wild type in HEK293 cells (Valdez-Flores et al. 2016). Based on the evidence, the p.Arg861Cys variant is classified as pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 861 of the SLC12A3 protein (p.Arg861Cys). This variant is present in population databases (rs373899077, gnomAD 0.02%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 21415153, 23328711, 26121437). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.2579C>T (Arg852Cys). ClinVar contains an entry for this variant (Variation ID: 437926). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 27582097). For these reasons, this variant has been classified as Pathogenic.

ACMG criteria used:PS3, PS4, PM1, PM3, PM5 , PP3, PP5

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gitelman syndrome (MIM#263800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (24 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated solute carrier family 12 domain (Decipher). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many patients with Gitelman syndrome (ClinVar, PMIDs: 9734597, 18391953, 26121437, 27872838). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using HEK293 cells showed the variant decreased SLC12A3 activity and SLC12A3 protein abundance in total cell lysate (PMID: 27582097). (SP) 1207 - Parental origin of the variant is unresolved, the variant is heterozygous in both parents (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The heterozygous p.Arg852Cys mutation in the SLC12A3 gene (NM_001126108.2:c.2554C>T) causes the 852th arginin amino acid  to be changed to cysteine. The p.Arg852Cys mutation can be found in population databases (rs373899077, gnomAD_genomes: 0.01%, number of homozygotes: 0). It has been described in the literature in several cases of SLC12A3 mutation-related disease (PMID: 27872838, 27582097, 26121437, 23328711, 22241817). Gitelman syndrome (#600968) linked to the SLC12A3 gene is inherited in an autosomal recessive (AR) manner.The patient is heterozygous for the p.Arg852Cys mutation, no second mutation in association with Gitelman-syndrome has been identified. Regarding the patient's phenotype and the mutation described above the patient diagnosed with Gitelman-syndrome.