ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.2191G>A (p.Gly731Arg)

gnomAD frequency: 0.00005  dbSNP: rs752101663
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV000762974 SCV000893417 pathogenic Familial hypokalemia-hypomagnesemia 2022-03-09 criteria provided, single submitter clinical testing
Invitae RCV000681801 SCV001202771 pathogenic not provided 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 731 of the SLC12A3 protein (p.Gly731Arg). This variant is present in population databases (rs752101663, gnomAD 0.004%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 12112667, 21415153, 25422309). 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: 562347). 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.
Genome-Nilou Lab RCV000762974 SCV002055348 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 RCV000762974 SCV002513815 pathogenic Familial hypokalemia-hypomagnesemia 2022-04-27 criteria provided, single submitter clinical testing ACMG criteria used:PS3, PS4, PM1, PM2, PM3, PP3, PP5
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center RCV000762974 SCV004190151 likely pathogenic Familial hypokalemia-hypomagnesemia 2020-04-13 criteria provided, single submitter clinical testing The c.2191G>A variant in the SLC12A3 gene is a heterozygous missense variant, which results in the substitution of the highly conserved glycine residue at the 731 position to arginine (p.Gly731Arg). This variant localizes to coding exon 18 of the SLC12A3 gene (26 exons total; NM_000339.3). This variant is predicted to be deleterious and damaging to protein structure and/or function based on in silico analyses (PROVEAN and SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (allele frequency = 0.00002837, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in multiple individuals with Gitelman syndrome either in the homozygous state or with another SLC12A3 variant (PMIDs: 17699451, 21415153, 30596175, 25422309).
Gharavi Laboratory, Columbia University RCV000681801 SCV000809268 likely pathogenic not provided 2018-09-16 no assertion criteria provided research
Natera, Inc. RCV000762974 SCV002089371 pathogenic Familial hypokalemia-hypomagnesemia 2020-09-30 no assertion criteria provided clinical testing

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