Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV001310259 | SCV002573224 | uncertain significance | Familial hypokalemia-hypomagnesemia | 2022-09-01 | criteria provided, single submitter | clinical testing | This missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.84). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. |
| Labcorp Genetics |
RCV003770625 | SCV004611268 | likely pathogenic | not provided | 2022-11-30 | criteria provided, single submitter | clinical testing | This variant is also known as c.2516A>T, p.Asp839Val. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp848 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16837915, 31183353, 33348466). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1012270). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 34046503). This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 848 of the SLC12A3 protein (p.Asp848Val). |
| Department of Traditional Chinese Medicine, |
RCV001310259 | SCV001481148 | uncertain significance | Familial hypokalemia-hypomagnesemia | 2021-02-03 | no assertion criteria provided | research | This mutation may cause structural changes of NCCT that destroy its biological effects, affect its reabsorption ability, and lead to electrolyte disorders. A functional deletion mutation of SLC12A3 encoding thiazide-sensitive NaCl cotransporter (NCCT) located in the distal convoluted tubules (DCT) of the kidney, which leads to dysfunction of sodium chloride reabsorption by the DCT, resulting in a series of pathophysiological changes and clinical manifestations such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. Several suspected pathogenic mutations were found near our newly discovered heterozygous mutant of Asp839Val (c.2516A>T): C.2490C>T (p.Thr830=), c.2495A>G (p.Asp832Gly), c.2532G>A (p.Trp844Ter), c.2510_2511del (p.Leu836_Phe837insTer), c.2514C>T (p.Asp838=), c.2521G>A (p.Gly841Ser), c.2533del (p.Leu845fs), and c.2546T>A (p.Leu849His) (https://www.ncbi.nlm.nih.gov/clinvar). These mutations can lead to protein product deletion or destruction, and we speculate that since c.2516A＞T(p. Asp839Val) is located in this region, it may also be a pathogenic mutation. |