ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.1195C>T (p.Arg399Cys)

gnomAD frequency: 0.00002  dbSNP: rs775931992
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000517680 SCV000615283 pathogenic not provided 2015-04-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000762972 SCV000893414 pathogenic Familial hypokalemia-hypomagnesemia 2021-12-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000517680 SCV000941626 pathogenic not provided 2023-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 399 of the SLC12A3 protein (p.Arg399Cys). This variant is present in population databases (rs775931992, gnomAD 0.003%). This missense change has been observed in individuals with Gitleman syndrome (PMID: 11168953, 17414160, 18391953, 25165177, 26121437). ClinVar contains an entry for this variant (Variation ID: 448391). 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%. This variant disrupts the p.Arg399 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 18391953, 23328711, 28469853), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000762972 SCV002020622 pathogenic Familial hypokalemia-hypomagnesemia 2021-10-22 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000762972 SCV002055331 pathogenic Familial hypokalemia-hypomagnesemia 2021-07-15 criteria provided, single submitter clinical testing
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP RCV000762972 SCV002513800 pathogenic Familial hypokalemia-hypomagnesemia 2022-04-27 criteria provided, single submitter clinical testing ACMG criteria used:PS1 PS4 PM1 PM2 PP3 PP4 PP5
Neuberg Centre For Genomic Medicine, NCGM RCV000762972 SCV004048283 pathogenic Familial hypokalemia-hypomagnesemia criteria provided, single submitter clinical testing The missense variant c.1195C>T, p.Arg399Cy in the SLC12A3 gene has previously been reported in homozygous and compound heterozygous state in individuals affected with Gitelman syndrome (Cruz DN et al., Kaito H et al.). This variant disrupts the p.Arg399 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (Berry MR et. al., Kaito H et al). The p.Arg399Cys variant is novel (not in any individuals) in 1000 Genomes and has frequency of 0.0012% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg399Cys in SLC12A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Arg399Cys variant is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000762972 SCV005204176 pathogenic Familial hypokalemia-hypomagnesemia 2024-06-20 criteria provided, single submitter clinical testing Variant summary: SLC12A3 c.1195C>T (p.Arg399Cys) 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 1.2e-05 in 247056 control chromosomes (gnomAD). c.1195C>T has been reported in the literature in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia (e.g. Demoulin_2014, Ashton_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25165177, 29398133). ClinVar contains an entry for this variant (Variation ID: 448391). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000762972 SCV001458493 pathogenic Familial hypokalemia-hypomagnesemia 2020-09-16 no assertion criteria provided clinical testing

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