Submission Details

KCNJ5 was first reported in relation to autosomal dominant familial hyperaldosteronism, type III in 2011 (Choi et al., PMID: 21311022). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found clear differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: hyperaldosteronism, familial, type III (OMIM: 613677) and long QT syndrome 13 (OMIM: 613485). The split curation for long QT syndrome 13 has been completed separately. 6 variants (all missense) that have been reported in at least 20 probands in 6 publications (PMID: 21311022, 22203740, 22308486, 22628607, 24420545, 24574546) are included in this curation. The mutations are all located near the pore/selectivity filter of the potassium channel. The mechanism of pathogenicity appears to be gain-of-function, with increased sodium conductance associated with loss of channel permeability, which leads to increased levels of aldosterone. This gene-disease relationship is also supported by experimental evidence (somatic mutations in humans, biochemical functional evidence, and expression-level evidence; PMID: 21311022 & GTEx expression data). The somatic mutations were counted in experimental evidence since they were not inherited and resemble a functional model in humans. GTEx expression-level evidence indicates very high expression in the adrenal gland. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 1/18/2024 (SOP Version 10).