Submissions for variant NM_001126108.2(SLC12A3):c.363G>C (p.Glu121Asp)

gnomAD frequency: 0.00102  dbSNP: rs146632606

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000681735	SCV000713176	uncertain significance	not provided	2024-01-29	criteria provided, single submitter	clinical testing	The p.Glu121Asp variant in SLC12A3 has been reported in the compound heterozygous state in 6 individuals with symptoms or a diagnosis of Gitelman syndrome or urinary stone disease, at least 4 of whom carried a second disease-causing SLC12A3 variant (Glaudemans 2012 PMID: 22009145, Berry 2013 PMID: 23328711, Groopman 2019 PMID: 30586318, Hureaux PMID: 31672324, Cogal 2021 PMID: 34805638). In at least one of these individuals, the reported levels of urinary calcium were normal. This variant has also been identified in 0.16% (110/68042) of European chromosomes by the Genome Aggregation Database (gnomAD v.3.1.2, http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 505768). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that the p.Glu121Asp variant may impact protein function (Glaudemans 2012 PMID: 22009145); however, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Glu121Asp variant is uncertain. ACMG/AMP Criteria applied: PM3_Strong, PS3_Supporting.
Illumina Laboratory Services, Illumina	RCV000778470	SCV000914725	likely pathogenic	Familial hypokalemia-hypomagnesemia	2019-01-09	criteria provided, single submitter	clinical testing	The SLC12A3 c.363G>C (p.Glu121Asp) variant has been reported in two studies and is found in a total of three probands with Gitelman syndrome in a compound heterozygous state (Glaudemans et al. 2012; Berry et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00132 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes demonstrated proper localization but sodium uptake was significantly reduced compared to wild type (Glaudemans et al. 2012). Based on the evidence, the p.Glu121Asp 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.
Fulgent Genetics, Fulgent Genetics	RCV000778470	SCV001752679	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-06-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000778470	SCV002055283	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000607947	SCV002598612	uncertain significance	not specified	2025-01-06	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.363G>C (p.Glu121Asp) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 250226 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in SLC12A3 causing Familial Hypokalemia-Hypomagnesemia, allowing no conclusion about variant significance. c.363G>C has been reported in the literature in individuals with Gitelman syndrome, at-least one of whom reported normal levels of urinary calcium (examples: Glaudemans_2012, and Berry 2013) and chronic kidney disease/urinary stone disease (example: Groopman_2019, Cogal_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypokalemia-Hypomagnesemia (Gitelman syndrome). At least one publication reports experimental evidence evaluating an impact on protein function in the Xenopus laevis oocyte system (example: Glaudemans_ 2012). The most pronounced variant effect results in approximately 30% of normal thiazide-sensitive NaCl cotransporter (NCC) activity and normal localization to the plasma membrane. The following publications have been ascertained in the context of this evaluation (PMID: 23328711, 34805638, 22009145, 30586318). ClinVar contains an entry for this variant (Variation ID: 505768). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681735	SCV003244111	uncertain significance	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 121 of the SLC12A3 protein (p.Glu121Asp). This variant is present in population databases (rs146632606, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 22009145, 23328711, 30586318, 31672324). ClinVar contains an entry for this variant (Variation ID: 505768). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC12A3 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 22009145). 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	RCV002529351	SCV003681065	uncertain significance	Inborn genetic diseases	2021-07-27	criteria provided, single submitter	clinical testing	The c.363G>C (p.E121D) alteration is located in exon 2 (coding exon 2) of the SLC12A3 gene. This alteration results from a G to C substitution at nucleotide position 363, causing the glutamic acid (E) at amino acid position 121 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000607947	SCV004027099	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000681735	SCV000809190	likely pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Natera, Inc.	RCV000778470	SCV001458483	uncertain significance	Familial hypokalemia-hypomagnesemia	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000607947	SCV001951956	benign	not specified		flagged submission	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000681735	SCV001973517	likely benign	not provided		flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003424170	SCV004106573	uncertain significance	SLC12A3-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The SLC12A3 c.363G>C variant is predicted to result in the amino acid substitution p.Glu121Asp. This variant has been reported with a second SLC12A3 variant in at least 6 individuals with presumed Gitelman Syndrome (Glaudemans et al. 2012. PubMed ID: 22009145; Berry et al. 2013. PubMed ID: 23328711; Hureaux et al. 2019. PubMed ID: 31672324, supplementary data; Groopman et al. 2019. PubMed ID: 30586318, supplementary data). One individual with suspected urinary stone disease also harbored this variant in the heterozygous state along with a SLC34A1 variant (PHN133, Cogal et al. 2021. PubMed ID: 34805638). Functional studies indicate that this variant affects the thiazide-sensitive NaCl cotransporter (NCC) activities through reducing the sodium uptake (Glaudemans et al. 2012. PubMed ID: 22009145). This amino acid position is moderately conserved and Asp is located at this position in Tetraodon (Alamut Visual Plus v1.6.1). This variant is reported in 0.16% of alleles in individuals of European (non-Finnish) descent in gnomAD V2. In the more recent gnomAD V4 data, this variant is observed in 2454/1,614,098 (0.15%) alleles and in 2 homozygotes, which may be too common to be a primary cause of disease (https://gnomad.broadinstitute.org/variant/16-56867150-G-C?dataset=gnomad_r4). Although we suspect this variant could possibly contribute to SLC12A3-related disorders, given the conflicting evidence, the clinical significance of this variant is uncertain.