ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.947G>T (p.Gly316Val)

gnomAD frequency: 0.00002  dbSNP: rs748920885
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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 RCV001939411 SCV002234250 pathogenic not provided 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 316 of the SLC12A3 protein (p.Gly316Val). This variant is present in population databases (rs748920885, gnomAD 0.01%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 12112667, 21415153). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1454114). 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: 17329572). This variant disrupts the p.Gly316 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17699451, 21415153, 30138938). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center RCV002290814 SCV002579450 likely pathogenic Familial hypokalemia-hypomagnesemia 2021-09-24 criteria provided, single submitter clinical testing
GeneDx RCV001939411 SCV005201609 pathogenic not provided 2023-12-27 criteria provided, single submitter clinical testing Published functional studies demonstrate defective transport activity (Riveira-Munoz et al., 2007); 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: 17329572, 12112667, 26921350, 21415153, 33348466, 35628451)

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