Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Baylor Genetics | RCV000122750 | SCV001524984 | pathogenic | Familial hyperaldosteronism type III | 2019-08-16 | criteria provided, single submitter | clinical testing | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Ambry Genetics | RCV002326795 | SCV002633414 | pathogenic | Cardiovascular phenotype | 2018-06-08 | criteria provided, single submitter | clinical testing | The p.G151R pathogenic mutation (also known as c.451G>A), located in coding exon 1 of the KCNJ5 gene, results from a G to A substitution at nucleotide position 451. The glycine at codon 151 is replaced by arginine, an amino acid with dissimilar properties. This alteration impacts the highly conserved ion selectivity filter (TIGYGF) located between transmembrane helices S5 and S6. This variant has been identified in multiple individuals with familial hyperaldosteronism type III (FH-III) and was reported to be de novo in several of them (Scholl UI et al. Proc. Natl. Acad. Sci. U.S.A. 2012;109:2533-8; Adachi M et al. Horm Res Paediatr. 2014;82:138-42; Monticone S et al. J Hum Hypertens. 2017;31:776-781). Functional studies suggest G151R leads to increased sodium conductance (Scholl UI et al. Proc. Natl. Acad. Sci. U.S.A. 2012;109:2533-8; Tauber P et al. Endocrinology. 2014;155:1353-62). In addition, internal structural analysis indicates that this variant disrupts the ion channel pore and is expected to eliminate the K+ selectivity of the K+ channel (Tao X et al. Science. 2009;326(5960):1668-74; Whorton MR and MacKinnon R. Cell. 2011;147(1):199-208; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV003531964 | SCV004295816 | pathogenic | Long QT syndrome | 2023-03-14 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly151 amino acid residue in KCNJ5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22203740, 22308486). 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 KCNJ5 protein function. ClinVar contains an entry for this variant (Variation ID: 91915). This missense change has been observed in individual(s) with clinical features of KCNJ5-related conditions (PMID: 22308486, 24819081). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 151 of the KCNJ5 protein (p.Gly151Arg). |
| Richard Lifton Laboratory, |
RCV000122472 | SCV000154980 | probable-pathogenic | not provided | no assertion criteria provided | not provided | Converted during submission to Likely pathogenic. | |
| OMIM | RCV000122749 | SCV000166006 | pathogenic | Aldosterone-producing adrenal adenoma, somatic | 2012-02-14 | no assertion criteria provided | literature only | |
| OMIM | RCV000122750 | SCV000166007 | pathogenic | Familial hyperaldosteronism type III | 2012-02-14 | no assertion criteria provided | literature only |