Submissions for variant NM_001126108.2(SLC12A3):c.247C>T (p.Arg83Trp)

gnomAD frequency: 0.00003  dbSNP: rs201255508

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000380828	SCV000398096	likely pathogenic	Familial hypokalemia-hypomagnesemia	2017-04-28	criteria provided, single submitter	clinical testing	The SLC12A3 c.247C>T (p.Arg83Trp) variant is reported in one study in which it is found in a compound heterozygous state with another missense variant in five patients with Gitelman syndrome (Vargas-Poussou et al. 2011). The p.Arg83Trp variant was absent from 200 control chromosomes and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium database. Based on the evidence, the p.Arg83Trp 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.
Invitae	RCV000809022	SCV000949158	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 83 of the SLC12A3 protein (p.Arg83Trp). This variant is present in population databases (rs201255508, gnomAD 0.006%). This missense change has been observed in individuals with SLC12A3-related conditions (PMID: 21415153). ClinVar contains an entry for this variant (Variation ID: 319889). 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). This variant disrupts the p.Arg83 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20675610, 21051746, 21415153). 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000380828	SCV001448790	likely pathogenic	Familial hypokalemia-hypomagnesemia	2019-09-06	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000380828	SCV002055320	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	RCV000380828	SCV002513856	pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS3, PM1, PM2, PP3, PP5, PM3
Fulgent Genetics, Fulgent Genetics	RCV000380828	SCV002811068	pathogenic	Familial hypokalemia-hypomagnesemia	2022-03-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000380828	SCV004027823	pathogenic	Familial hypokalemia-hypomagnesemia	2023-05-05	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM3,PM5,PM2_SUP,PP4