Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001210434 | SCV001381922 | pathogenic | not provided | 2023-09-15 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC12A3 protein function. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 623 of the SLC12A3 protein (p.Leu623Pro). 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 missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8954067, 12008755, 17044667, 17329572, 30596175). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8595). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000009126 | SCV004037980 | pathogenic | Familial hypokalemia-hypomagnesemia | 2023-08-18 | criteria provided, single submitter | clinical testing | Variant summary: SLC12A3 c.1868T>C (p.Leu623Pro) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain (IPR004841) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-06 in 163202 control chromosomes (gnomAD). c.1868T>C has been reported in the literature in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia with evidence of cosegregation with disease (Takeuchi_1996, Riveira-Munoz_2007, Mori_2021), and some patients were reported as compound heterozygous with other (likely) pathogenic or truncating variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8954067, 17329572, 33348466). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Revvity Omics, |
RCV000009126 | SCV004238357 | pathogenic | Familial hypokalemia-hypomagnesemia | 2023-01-26 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000009126 | SCV000029343 | pathogenic | Familial hypokalemia-hypomagnesemia | 1996-12-01 | no assertion criteria provided | literature only |