Submissions for variant NM_001126108.2(SLC12A3):c.1387G>A (p.Gly463Arg)

gnomAD frequency: 0.00004  dbSNP: rs374163823

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000286818	SCV000398114	likely pathogenic	Familial hypokalemia-hypomagnesemia	2017-04-28	criteria provided, single submitter	clinical testing	The SLC12A3 c.1387G>A (p.Gly463Arg) missense variant has been reported in three studies in which it is found in two patients with Gitelman syndrome in a compound heterozygous state, one with a second missense variant and one with a deletion variant (Nicolet-Barousse et al. 2005; Vargas-Poussou et al. 2011). Valdez-Flores et al. (2016) report four unrelated families described as carrying the p.Gly463Arg variant. No details of the number of affected individuals or zygosity of the variant are given. Control data are unavailable for the p.Gly463Arg variant which is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated in transfected HEK293 cells that the p.Gly463Arg variant caused significantly lower enzyme activity compared to wild type. Immunoblot assays also showed the p.Gly463Arg variant led to decreased protein expression and abundance in the plasma membrane (Valdez-Flores et al. 2016). Based on the evidence, the p.Gly463Arg 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.
GeneDx	RCV000414425	SCV000491147	likely pathogenic	not provided	2020-02-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a marked reduction in thiazide-sensitive NaCl cotransporter activity in cells expressing G463R compared to cells expressing wild-type protein (Valdez-Flores et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21415153, 27582097, 31672324, 32140910)
Invitae	RCV000414425	SCV001583459	pathogenic	not provided	2023-12-09	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 463 of the SLC12A3 protein (p.Gly463Arg). This variant is present in population databases (rs374163823, gnomAD 0.006%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 15824853, 21415153, 31672324). ClinVar contains an entry for this variant (Variation ID: 319903). 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	RCV000286818	SCV002055333	likely 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	RCV000286818	SCV002513804	pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS3, PS4, PM1, PM2,PM5 PP3, PP5
Fulgent Genetics, Fulgent Genetics	RCV000286818	SCV002778223	pathogenic	Familial hypokalemia-hypomagnesemia	2022-05-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000414425	SCV001926702	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000414425	SCV001958169	likely pathogenic	not provided		no assertion criteria provided	clinical testing