ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.1175C>T (p.Thr392Ile)

gnomAD frequency: 0.00002  dbSNP: rs748575829
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001381399 SCV001579777 pathogenic not provided 2023-08-21 criteria provided, single submitter clinical testing This variant is present in population databases (rs748575829, gnomAD 0.01%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 392 of the SLC12A3 protein (p.Thr392Ile). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 17699451, 20552229, 20675610, 22009145). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr392 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 26770037), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 22009145). 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: 1069509).
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP RCV002243171 SCV002513799 likely pathogenic Familial hypokalemia-hypomagnesemia 2022-04-27 criteria provided, single submitter clinical testing ACMG criteria used:PS4 PM1 PM2 PP5
Revvity Omics, Revvity RCV002243171 SCV003827930 pathogenic Familial hypokalemia-hypomagnesemia 2021-12-30 criteria provided, single submitter clinical testing

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