ClinGen Dosage Sensitivity Curation Page

CLCN5

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
15086899 32 unrelated males with a clinical diagnosis of Dent's disease underwent sequencing of CLCN5. Sixteen mutations were found in 19/32 individuals with 10 missense, 4 nonsense, and 2 frameshift mutations described.
22083641 In this review by Lourdel et al. (2012), 148 previously reported mutations in CLCN5 associated with Dent's disease were summarized. Of the 148 mutations reported, 36% were nonsense mutations, 30% missense mutations, 18% deletion mutations, 7% splice site mutations, and 6% insertional mutations. These mutations are divided into 3 categories depending on their effect on protein function. Functional studies and animal models are also summarized.

Haploinsufficiency phenotype comments:

Mutations in CLCN5 account for approximately 60% of Dent's disease, a proximal renal tubular dysfunction, which is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease (CKD).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.