Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001379907 | SCV001577805 | pathogenic | not provided | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 135 of the SLC12A3 protein (p.Arg135Cys). This variant is present in population databases (rs749742102, gnomAD 0.01%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 21415153, 31672324). ClinVar contains an entry for this variant (Variation ID: 1068374). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg135 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21631963). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002499787 | SCV002809746 | likely pathogenic | Familial hypokalemia-hypomagnesemia | 2024-06-17 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002550965 | SCV003571877 | likely pathogenic | Inborn genetic diseases | 2021-08-27 | criteria provided, single submitter | clinical testing | The c.403C>T (p.R135C) alteration is located in exon 2 (coding exon 2) of the SLC12A3 gene. This alteration results from a C to T substitution at nucleotide position 403, causing the arginine (R) at amino acid position 135 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (14/245644) total alleles studied. The highest observed frequency was 0.01% (4/30286) of South Asian alleles. This variant has been reported in several individuals with Gitelman syndrome in conjunction with a second SLC12A3 variant (Vargas-Poussou, 2011; Glaudemans, 2012; Hureaux, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |
| Gene |
RCV001379907 | SCV005201608 | uncertain significance | not provided | 2023-09-27 | criteria provided, single submitter | clinical testing | Observed with a pathogenic variant, phase unknown, in patients with features suggestive of Gitelman syndrome in the literature, although additional clinical information was not provided (Vargas-Poussou et al., 2011; Hureaux et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21415153, 31672324, 22009145) |
| Mayo Clinic Laboratories, |
RCV001379907 | SCV005414348 | likely pathogenic | not provided | 2023-09-28 | criteria provided, single submitter | clinical testing | PP3, PM2, PM3_strong, PS4_moderate |