Submissions for variant NM_001126108.2(SLC12A3):c.473G>A (p.Arg158Gln)

gnomAD frequency: 0.00004  dbSNP: rs1274973729

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802180	SCV000941998	pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 158 of the SLC12A3 protein (p.Arg158Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Gitelman syndrome (PMID: 12112667, 21415153, 25852896, 30413979). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 647629). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001251514	SCV001427186	pathogenic	Familial hypokalemia-hypomagnesemia	2019-03-17	criteria provided, single submitter	clinical testing	A homozygous missense variant, NM_000339.2(SLC12A3):c.473G>A, has been identified in exon 3 of 26 of the SLC12A3 gene. The variant is predicted to result in a minor amino acid change from arginine to glutamine at position 158 of the protein ( NP_000330.2(SLC12A3):p.(Arg158Gln)). The arginine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the SLC12 superfamily functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.001% (4 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic in patients with Gitelman syndrome (Syren, M. et al. (2002), Larkins, N. et al. (2014), Zhong, F. et al. (2018)). It has also been shown to segregate with the disease in 2 families (Larkins, N. et al. (2014), Zhong, F. et al. (2018)). A different variant in the same codon resulting in a change to leucine as also been shown to cause Gitelman syndrome (Glaudemans, B. et al. (2012)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Genome-Nilou Lab	RCV001251514	SCV002055322	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	RCV001251514	SCV002513867	pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS4, PM2, PM3, PM5, PP3, PP5
Fulgent Genetics, Fulgent Genetics	RCV001251514	SCV002806682	pathogenic	Familial hypokalemia-hypomagnesemia	2021-10-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001251514	SCV004238358	pathogenic	Familial hypokalemia-hypomagnesemia	2023-07-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000802180	SCV005079291	pathogenic	not provided	2024-06-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on SLC12A3 expression, localization and ion transport (PMID: 36370249); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 12112667, 35628451, 25852896, 30413979, 32939031, 31577716, 21415153, 32926342, 36370249, 36964972)