Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000800647 | SCV000940376 | pathogenic | not provided | 2023-09-08 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Cys396*) in the SLC12A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SLC12A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 646369). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002282370 | SCV002570579 | likely pathogenic | Familial hypokalemia-hypomagnesemia | 2022-07-19 | criteria provided, single submitter | clinical testing | Variant summary: SLC12A3 c.1188C>A (p.Cys396X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar (e.g. c.2505G>A (p.Trp835*), c.3025C>T (p.Arg1009*)) . The variant allele was found at a frequency of 4.1e-06 in 244578 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1188C>A in individuals affected with Familial Hypokalemia-Hypomagnesemia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted an assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Regional Center For Medical Genetics Timis, |
RCV002282370 | SCV005077950 | likely pathogenic | Familial hypokalemia-hypomagnesemia | 2024-07-05 | criteria provided, single submitter | research | This variant is present with low frequency healthy population databases (gnomAD v4.1.0 exomes, f = 0.000002485). This variant leads to premature stop codon occurrence and loss of function (LOF). SLC12A3-LOF variants are known to be pathogenic. Therefore, the variant was classified as likely pathogenic, according to ACMG 2015 guidelines. However, a definitive diagnosis of Gitelman syndrome could not be established in this case, since only this truncating variant was identified in our patient. Of note, sequencing (clinical exome) was performed under the clinical suspicion of Bartter syndrome. |