The CLCN5 gene is located on chromosome X at p11.23 and encodes the chloride voltage-gated channel 5 protein, a chloride/proton exchanger primarily located in the endosomal membranes of proximal renal tubular cells. This protein is important for the acidification of early endosomes of proximal tubules and the re-absorption of low-molecular-weight proteins in the proximal tubule
Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism, inheritance pattern and phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: Dent disease 1 (OMIM:300009), hypophosphatemic rickets (OMIM:300554), nephrolithiasis, type 1 (OMIM:310468) and proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis (OMIM:308990). The preferred disease name suggested for this grouping of disorders is ‘Dent disease - CLCN5’.
CLCN5 was first reported in relation to X-linked recessive Dent disease 1 in 1994 (Fisher et al., PMID: 7874126). The mechanism of pathogenicity is known to be loss of function. Dent disease 1 usually presents in childhood with low molecular weight proteinuria, hypercalciuria and additional features such as hypophosphatemia, nephrocalcinosis, nephrolithisasis, haematuria, renal insufficiency, bony deformities and short stature.
At least 10 variants (7 nonsense, 1 canonical splice site, 2 missense) have been reported in 10 probands over 5 publications (PMIDs: 8559248, 30581818, 29084614, 9734595, 16822791 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data.
This gene-disease relationship is also supported by expression studies and animal models. CIC-5 was shown to co-localise with the proton pump and endocytosed beta2-macroglobulin in the proximal tubule of rat kidney cells and the intercalating cells of the collecting duct (PMID: 9653142). Hemizygous clcn5 knockout mice models recapitulated the human disease phenotype (PMIDs: 11099045, 15942052). A total of 4.5/6 pts. for experimental evidence was reached.
In summary, there is definitive evidence supporting the relationship between CLCN5 and X-linked recessive Dent Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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