Submissions for variant NM_001126108.2(SLC12A3):c.2803C>T (p.Arg935Trp)

gnomAD frequency: 0.00023  dbSNP: rs56125220

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001120239	SCV001278715	uncertain significance	Familial hypokalemia-hypomagnesemia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002556571	SCV003274577	uncertain significance	not provided	2022-08-21	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 944 of the SLC12A3 protein (p.Arg944Trp). This variant is present in population databases (rs56125220, gnomAD 0.03%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 31672324). ClinVar contains an entry for this variant (Variation ID: 887481). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002556572	SCV003626912	uncertain significance	Inborn genetic diseases	2022-06-30	criteria provided, single submitter	clinical testing	The c.2830C>T (p.R944W) alteration is located in exon 24 (coding exon 24) of the SLC12A3 gene. This alteration results from a C to T substitution at nucleotide position 2830, causing the arginine (R) at amino acid position 944 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004746242	SCV005351756	uncertain significance	SLC12A3-related disorder	2024-09-09	no assertion criteria provided	clinical testing	The SLC12A3 c.2830C>T variant is predicted to result in the amino acid substitution p.Arg944Trp. This variant was reported with a pathogenic SLC12A3 variant in an individual with Gitelman syndrome (Supp. Table 1 Hureaux M et al 2019. PubMed ID: 31672324). This variant was also reported in the heterozygous state without a second SLC12A3 in a patient with clinical suspicion of Gitelman syndrome (Supp. Table 1 Glaudemans et al 2012. PubMed ID: 22009145). This variant is reported in 0.028% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.