Submissions for variant NM_001126108.2(SLC12A3):c.1181G>A (p.Gly394Asp)

dbSNP: rs777815715

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001310329	SCV001500078	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001310329	SCV002181236	pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 394 of the SLC12A3 protein (p.Gly394Asp). 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 individual(s) with Gitelman syndrome (PMID: 29925901, 30138938, 35628451). 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: 1012400). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 29925901). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002286834	SCV002577431	pathogenic	Familial hypokalemia-hypomagnesemia	2022-07-26	criteria provided, single submitter	clinical testing	PS3, PM2, PM5, PP2, PP3, PP5
Ambry Genetics	RCV002545034	SCV003625576	likely pathogenic	Inborn genetic diseases	2022-06-10	criteria provided, single submitter	clinical testing	The c.1181G>A (p.G394D) alteration is located in exon 10 (coding exon 10) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 1181, causing the glycine (G) at amino acid position 394 to be replaced by an aspartic acid (D). This variant impacts the first base pair of coding exon 10. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in the compound heterozygous state with a second pathogenic SLC12A3 variant in multiple individuals with Gitelman syndrome (Ravarotto, 2018; Huang, 2018). This amino acid position is highly conserved in available vertebrate species. Functional studies show this variant leads to impaired localization with retention and degradation in the endoplasmic reticulum (Ravarotto, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.