Database of CLCN5 Pathogenic Variants Causing Dent Disease

Dent disease type 1 is an X-linked proximal tubulopathy caused by pathogenic variants in CLCN5, which encodes the chloride/proton exchanger, ClC-5. Loss of ClC-5 function disrupts receptor-mediated endocytosis, resulting in low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive kidney failure. Although many CLCN5 variants have been reported, existing resources remain incomplete, inconsistent, or based on different reference sequences (RefSeqs), thereby hindering variant comparison and clinical interpretation. A comprehensive and uniformly annotated catalog is needed to improve diagnostic accuracy and estimates of Dent disease type 1 prevalence.

Potentially pathogenic CLCN5 variants were compiled from firsthand Dent disease type 1 case reports, variant databases, Dent disease type 1-related online resources, and unpublished patients. Variants representing experimental constructs or benign or likely benign changes were excluded. All variants were standardized using The Human Genome Variation Society (HGVS) nomenclature and mapped to RefSeqs NM_001127898.4 and NM_000084.5 using Mutalyzer. Pathogenicity was assessed and cross-validated with the literature and public databases.

We identified 524 unique pathogenic or likely pathogenic variants, exceeding all existing databases. Variant types included missense (31%), InDel insertions and deletions (37%), nonsense (14%), splicing defects (13%), and large deletions (5%). Most variants (74%) were reported only once. Exon 10 (NM_001127898.4) showed the highest density of pathogenic variants, driven by missense and in-frame insertions and deletions (InDel). Structural mapping revealed functional restrained regions in Helix H and O-Q helices. Source-variant counts indicated a minimum of 880 affected families, suggesting approximately 3520 globally.

This uniformly annotated catalog-the most comprehensive to date-enhances interpretation of CLCN5 variants, refines Dent disease type 1 burden estimates, and identifies key functional regions relevant for therapeutic development.