Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000986255 | SCV001135194 | pathogenic | Bartter disease type 3 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002549662 | SCV003523169 | pathogenic | not provided | 2022-10-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCNKB function (PMID: 31803959). 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 CLCNKB protein function. ClinVar contains an entry for this variant (Variation ID: 801449). This missense change has been observed in individual(s) with Bartter syndrome (PMID: 21865213, 28381550, 31834604). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 437 of the CLCNKB protein (p.Gly437Arg). |
| Sydney Genome Diagnostics, |
RCV001328286 | SCV001449237 | uncertain significance | Bartter disease type 3; Bartter disease type 4B | 2018-10-24 | no assertion criteria provided | clinical testing | This patient is homozygous for the variant of uncertain clinical significance, c.1309G>A (p.Gly437Arg), in the CLCNKB gene. This variant has been previously reported in a compound heterozygous state with another CLCNKB variant in a patient with classic Bartter syndrome (type 3) (Lee et al 2011, Nephrol Dial Transplant; 0:1-6). However, no functional studies were performed on this variant. p.Gly437 is a highly conserved amino acid (up to 13 species) and there is a moderate physicochemical difference between the wild type glycine and the mutant arginine. In silico analysis (Alamutv2.6) using varies in regards to this variant; while Align GVGD and SIFT predict this variant to be tolerated, PolyPhen2 and Mutation Taster suggest that this variant is likely to be pathogenic. |