Submissions for variant NM_001126108.2(SLC12A3):c.2863C>T (p.Arg955Trp)

gnomAD frequency: 0.00006  dbSNP: rs559626481

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000341379	SCV000398144	likely pathogenic	Familial hypokalemia-hypomagnesemia	2017-04-28	criteria provided, single submitter	clinical testing	The SLC12A3 c.2890C>T (p.Arg964Trp) missense variant has been reported in one study in which it was found in three unrelated patients with Gitelman syndrome in a compound heterozygous state with a second missense variant (Vargas-Poussou et al. 2011). The p.Arg964Trp variant was absent from 420 control chromosomes and is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Arg964 residue is conserved. Another missense variant at the same amino acid position (p.Arg964Gln) has also been observed in patients. Based on the evidence, the p.Arg964Trp 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	RCV001389305	SCV001590621	pathogenic	not provided	2024-01-26	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 964 of the SLC12A3 protein (p.Arg964Trp). This variant is present in population databases (rs559626481, gnomAD 0.006%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 21415153, 31672324). 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: 319919). 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%. This variant disrupts the p.Arg964 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528245, 17654016, 21415153, 22214629, 30596175). 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.
Genome-Nilou Lab	RCV000341379	SCV002055354	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001389305	SCV003840616	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	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: 31589614, 33306824, 21415153, 31672324, 28844315)
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328102	SCV001449423	likely pathogenic	Familial hypokalemia-hypomagnesemia; Bartter syndrome	2018-10-24	no assertion criteria provided	clinical testing	This patient is heterozygous for a likely pathogenic variant, c.2890C>T p.(Arg964Trp), in the SLC12A3 gene. This variant has been reported in the ExAC database (http://exac.broadinstitute.org/) with a very low allele frequency of 0.0041% (5 out of 121408 alleles). This variant has been previously reported in trans with other SLC12A3 variants in patients with Gitelman syndrome in the literature (Vargas-Poussou et al 2011 J Am Soc Nephrol 22:693-703).