ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.1315G>A (p.Gly439Ser)

gnomAD frequency: 0.00009  dbSNP: rs759377924
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000713326 SCV000843922 pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000760979 SCV000890885 pathogenic Familial hypokalemia-hypomagnesemia 2018-05-23 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000760979 SCV000893416 pathogenic Familial hypokalemia-hypomagnesemia 2018-10-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000760979 SCV000914727 pathogenic Familial hypokalemia-hypomagnesemia 2019-01-11 criteria provided, single submitter clinical testing Across a selection of the available literature, the SLC12A3 c.1315G>A (p.Gly439Ser) missense variant was found in a total of 15 individuals affected with Gitelman syndrome (GS). The p.Gly439Ser variant was found in a homozygous state in two individuals (one of whom was also homozygous for a second variant), in a compound heterozygous state in 12 individuals (including two siblings), and in a heterozygous state in one individual in whom a second variant was not identified (Mastroianni et al. 1996; Melander et al. 2000; Urbanová et al. 2006; Tajima et al 2006; Favre et al. 2012; Berry et al. 2013; Brambilla et al. 2013; Bouchireb et al. 2014). The variant was found in a heterozygous state in one of 844 control chromosomes and is reported at a frequency of 0.0004 in the non-Finnish European population of the Exome Aggregation Consortium. De Jong et al. (2002) demonstrated that Xenopus oocytes expressing the p.Gly439Ser variant showed no significant sodium uptake and exhibited significant cellular mislocalization of the protein. Based on the collective evidence, the p.Gly439Ser variant is classified as pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000713326 SCV001215908 pathogenic not provided 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 439 of the SLC12A3 protein (p.Gly439Ser). This variant is present in population databases (rs759377924, gnomAD 0.03%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 17654016, 23475471, 25112827). 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: 586601). 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: 12039972). For these reasons, this variant has been classified as Pathogenic.
Molecular Biology Laboratory, Fundació Puigvert RCV000760979 SCV001425254 pathogenic Familial hypokalemia-hypomagnesemia 2020-02-01 criteria provided, single submitter research
GeneDx RCV000713326 SCV001795125 pathogenic not provided 2023-08-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect due to an intracellular trafficking defect, with failure to reach the cell membrane (De Jong et al., 2002); 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: 17159356, 19451210, 19349556, 17654016, 24790334, 28700713, 28469853, 23475471, 12039972, 8900229, 25112827, 26830254, 23328711, 18391953, 15102966, 10988270, 31672324, 26121437, 22241817, 22009145, 31398183, 31589614, 33348466)
Revvity Omics, Revvity Omics RCV000760979 SCV002020621 pathogenic Familial hypokalemia-hypomagnesemia 2022-06-29 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000760979 SCV002055332 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 RCV000760979 SCV002513802 pathogenic Familial hypokalemia-hypomagnesemia 2022-04-27 criteria provided, single submitter clinical testing ACMG criteria used:PM1 PM2 PM3 PP3 PP5
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328223 SCV001449437 pathogenic Familial hypokalemia-hypomagnesemia; Bartter syndrome 2019-08-27 no assertion criteria provided clinical testing This individual is heterozygous for the c.1315G>A variant in the SLC12A3 gene, which results in the amino acid substitution of glycine to serine at residue 439, p.(Gly439Ser). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.015% (42 out of 276,658 alleles).This variant has been previously described in multiple individuals with Gitelman syndrome, in either a homozygous or compound heterozygous state (Bouchireb et al 2014 BMC Pediatrics 14: 201; Vargas-Poussou et al 2011 J Am Soc Nephrol 22: 693-703). In addition, functional studies, using Xenopus oocytes harbouring the p.(Gly439Ser) variant, showed a loss of sodium ion uptake and exhibited significant cellular mis-localisation of the protein (De Jong et al 2002 J Am Soc Nephrol 13: 1442-1448). This variant is considered to be pathogenic according to the ACMG guidelines. (Evidence used: PS3, PM2, PM3_strong).
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000713326 SCV001930373 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000713326 SCV001952291 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV000760979 SCV002089349 pathogenic Familial hypokalemia-hypomagnesemia 2020-10-10 no assertion criteria provided clinical testing

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