Submissions for variant NM_001126108.2(SLC12A3):c.2938G>A (p.Gly980Arg)

gnomAD frequency: 0.00005  dbSNP: rs34803727

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000713331	SCV000843928	pathogenic	not provided	2018-04-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762975	SCV000893419	likely pathogenic	Familial hypokalemia-hypomagnesemia	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000713331	SCV000936874	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 989 of the SLC12A3 protein (p.Gly989Arg). This variant is present in population databases (rs34803727, gnomAD 0.01%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 17329572, 18391953, 21415153, 23328711, 29942493). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2938G>A (G980R). ClinVar contains an entry for this variant (Variation ID: 586605). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC12A3 protein function. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 12039972). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000762975	SCV002055356	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000713331	SCV002064218	pathogenic	not provided	2022-01-06	criteria provided, single submitter	clinical testing	In vitro functional analysis demonstrated significantly diminished metolazone-sensitive sodium uptake levels in cells harboring this variant; immunocytochemical analysis revealed that the altered protein was localized to the cytoplasm and plasma membrane rather than only the plasma membrane as observed with the wild-type protein (De Jong et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as p.(G980R); This variant is associated with the following publications: (PMID: 23328711, 21415153, 11168953, 22009145, 31672324, 33144682, 17329572, 29942493, 18391953, 12039972)
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	RCV000762975	SCV002513828	pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS3, PS4, PM1, PM2, PM3, PP1, PP5
Revvity Omics, Revvity	RCV000762975	SCV003814057	likely pathogenic	Familial hypokalemia-hypomagnesemia	2022-02-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004026827	SCV004951090	pathogenic	Inborn genetic diseases	2020-11-12	criteria provided, single submitter	clinical testing	The c.2965G>A (p.G989R) alteration is located in exon 26 (coding exon 26) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 2965, causing the glycine (G) at amino acid position 989 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the SLC12A3 c.2965G>A alteration was observed in 0.006% (17/282,386) of total alleles studied, with a frequency of 0.01% (14/128,704) in the European (non-Finnish) subpopulation. This alteration has been reported in multiple patients with Gitelman syndrome in both the homozygous and compound heterozygous states (Berry, 2013; Glaudemans, 2012; Vargas-Poussou, 2011; Ji, 2008). This amino acid position is not well conserved in available vertebrate species. In an assay of metolazone-sensitive sodium uptake this variant was found to be functionally abnormal (de Jong, 2002). The in silico prediction for the p.G989R alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000762975	SCV005086059	pathogenic	Familial hypokalemia-hypomagnesemia	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gitelman syndrome (MIM#263800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 17 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated SLC12 family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical diagnostic laboratories and is associated with Gitelman syndrome (ClinVar, PMID: 11168953). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328220	SCV001449434	pathogenic	Familial hypokalemia-hypomagnesemia; Bartter syndrome	2018-07-13	no assertion criteria provided	clinical testing	This individual is heterozygous for the c.2965G>A variant in the SLC12A3 gene. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.006% (16 out of 276,718 alleles). The c.2965G>A p.(Gly989Arg) variant, which is equivalent to c.2938G>A p.(Gly980Arg) using transcript NM_001126108.1, has been described in many patients with Gitelman syndrome as compound heterozygous with a second pathogenic variant (e.g. De Jong et al. 2002 J Am Soc Nephrol 13: 1442-1448; Riveira-Munoz et al. 2007 J Am Soc Nephrol 18: 1271-1283; Ji et al. 2008 Nat Genet 40: 592-599). Functional studies found that the mutant protein had impaired sodium ion uptake and was also partially incorrectly localised in the cytoplasm (De Jong et al. 2002 J Am Soc Nephrol 13: 1442-1448). This variant is considered to be pathogenic according to the ACMG guidelines.
Natera, Inc.	RCV000762975	SCV001452598	pathogenic	Familial hypokalemia-hypomagnesemia	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000713331	SCV001928800	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000713331	SCV001967258	likely pathogenic	not provided		no assertion criteria provided	clinical testing