Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001067249 | SCV001232298 | pathogenic | not provided | 2023-08-19 | criteria provided, single submitter | clinical testing | 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: 860860). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 12112667, 21628937, 30596175). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs771326058, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 677 of the SLC12A3 protein (p.Val677Met). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001827438 | SCV003934457 | pathogenic | Familial hypokalemia-hypomagnesemia | 2023-05-26 | criteria provided, single submitter | clinical testing | Variant summary: SLC12A3 c.2029G>A (p.Val677Met) results in a conservative amino acid change to a highly conserved residue located in the SLC12A transporter, C-terminal (IPR018491) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250930 control chromosomes (gnomAD). c.2029G>A has been reported in the literature in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia (Gitelman syndrome, Fujimura_2019, Syrn_2019, Yagi_2011, Zhang_2021), and several were reported as compound hererozygous with other (likely) pathogenic 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: 12112667, 33996672, 21628937, 30596175). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Natera, |
RCV001827438 | SCV002089367 | pathogenic | Familial hypokalemia-hypomagnesemia | 2021-03-12 | no assertion criteria provided | clinical testing |