ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.1390G>A (p.Ala464Thr)

gnomAD frequency: 0.00006  dbSNP: rs201945662
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778472 SCV000914728 likely pathogenic Familial hypokalemia-hypomagnesemia 2017-12-18 criteria provided, single submitter clinical testing The SLC12A3 c.1390G>A (p.Ala464Thr) variant has been reported in ten individuals with Gitelman syndrome (Syrén et al. 2002; Colussi et al. 2007; Vargas-Poussou et al. 2011; Balavoine et al. 2011; Glaudemans et al. 2012; Berry et al. 2013), including in a homozygous state in one patient, in a compound heterozygous state in four patients, and in a heterozygous state in five patients in whom a second variant was not identified. Vargas-Poussou et al. (2011) note that 18 to 40% of patients with suspected Gitelman syndrome carry only one SLC12A3 variant allele. The p.Ala464Thr variant was absent from 100 control alleles and is reported at a frequency of 0.000012 in the Total population of the Genome Aggregation Database. Functional studies of the variant have not been conducted. Based on the collective evidence, the p.Ala464Thr variant is classified as likely pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp RCV001224209 SCV001396393 pathogenic not provided 2024-02-24 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 464 of the SLC12A3 protein (p.Ala464Thr). This variant is present in population databases (rs201945662, gnomAD 0.007%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 17699451, 21415153, 21753071, 22009145). ClinVar contains an entry for this variant (Variation ID: 631753). 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 80%. For these reasons, this variant has been classified as Pathogenic.
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP RCV000778472 SCV002513806 likely pathogenic Familial hypokalemia-hypomagnesemia 2022-04-27 criteria provided, single submitter clinical testing ACMG criteria used:PS4, PM1, PM2, PP3, PP5,
Fulgent Genetics, Fulgent Genetics RCV000778472 SCV002800232 likely pathogenic Familial hypokalemia-hypomagnesemia 2023-12-28 criteria provided, single submitter clinical testing
Natera, Inc. RCV000778472 SCV002089350 likely pathogenic Familial hypokalemia-hypomagnesemia 2020-03-29 no assertion criteria provided clinical testing

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