Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000607947 | SCV000713176 | uncertain significance | not specified | 2018-12-26 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu121Asp variant in SLC12A3 has been reported in 3 individuals with autosomal recessive Gitelman syndrome, at least two of whom carried a second disease-causing SLC12A3 variant (Glaudemans, 2012, Berry 2013). In vitro functional studies provide som e evidence that the p.Glu121Asp variant may impact protein function (Glaudemans, 2012). However, these types of assays may not accurately represent biological f unction. This variant has also been identified in 0.16% (209/128370) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org). Although this variant has been seen in the general population, its f requency is not high enough to rule out a pathogenic role. In summary, while the re is some suspicion for a pathogenic role, the clinical significance of the p.G lu121Asp variant is uncertain. ACMG/AMP Criteria applied: PM3_Strong, PS3_Suppor ting. |
Illumina Laboratory Services, |
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, |
RCV000778470 | SCV001752679 | likely pathogenic | Familial hypokalemia-hypomagnesemia | 2021-06-30 | criteria provided, single submitter | clinical testing | |
Genome- |
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, |
RCV000607947 | SCV002598612 | uncertain significance | not specified | 2022-09-07 | 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. Five of five 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 does not allow conclusions 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
Invitae | RCV000681735 | SCV003244111 | uncertain significance | not provided | 2022-09-19 | 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, 31672324). ClinVar contains an entry for this variant (Variation ID: 505768). 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 not expected to disrupt SLC12A3 protein function. 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, |
RCV000607947 | SCV004027099 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV003424170 | SCV004106573 | uncertain significance | SLC12A3-related condition | 2023-04-04 | criteria provided, single submitter | clinical testing | The SLC12A3 c.363G>C variant is predicted to result in the amino acid substitution p.Glu121Asp. This variant has been reported to be causative for autosomal recessive 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 second established causative variant in SLC12A3 (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 variant is reported in 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56901062-G-C). This variant is interpreted as likely pathogenic. |
Gharavi Laboratory, |
RCV000681735 | SCV000809190 | likely pathogenic | not provided | 2018-09-16 | no assertion criteria provided | research | |
Natera, |
RCV000778470 | SCV001458483 | uncertain significance | Familial hypokalemia-hypomagnesemia | 2020-09-16 | no assertion criteria provided | clinical testing | |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000607947 | SCV001951956 | benign | not specified | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000681735 | SCV001973517 | likely benign | not provided | no assertion criteria provided | clinical testing |