ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.625C>T (p.Arg209Trp)

gnomAD frequency: 0.00001  dbSNP: rs28936388
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001381397 SCV001579775 pathogenic not provided 2023-09-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg209 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11168953, 21415153, 23328711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 10516289). 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. ClinVar contains an entry for this variant (Variation ID: 8586). This missense change has been observed in individual(s) with clinical features of Gitelman syndrome (PMID: 8528245, 31672324). 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 present in population databases (rs28936388, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 209 of the SLC12A3 protein (p.Arg209Trp).
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP RCV000009117 SCV002513793 pathogenic Familial hypokalemia-hypomagnesemia 2022-04-27 criteria provided, single submitter clinical testing ACMG criteria used:PS4 PM1 PM2 PM3 PP3
OMIM RCV000009117 SCV000029334 pathogenic Familial hypokalemia-hypomagnesemia 1996-01-01 no assertion criteria provided literature only
Natera, Inc. RCV000009117 SCV002089332 pathogenic Familial hypokalemia-hypomagnesemia 2021-02-11 no assertion criteria provided clinical testing

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