ClinGen Dosage Sensitivity Curation Page

OCRL

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
10923037 Monnier et al. (2000) performed mutation analysis in 36 French families with Lowe?s syndrome and characterized 27 new truncating variants (de novo or inherited), including frameshift, nonsense, splice site mutations, and large genomic deletions besides other 1 in-frame and 6 missense variants. One nonsense variant (R483X) was a recurrent variant. The four large genomic deletions occurred in the first half of the gene, whereas all the remaining mutations took place in the second part of the gene and were concentrated in a few exons.
21031565 Hichri et al. (2011) A French cohort study identified a OCRL gene variant in 130 Lowe syndrome families and 6 families affected by Dent-2 disease. 51 of the identified variants were novel. No founding effect was evidenced for recurrent mutations. Among them were 2 partial gene deletions, 7 nonsense, 9 splicing and 12 frame shift variants. Majority of these truncating variants were identified in patients with Lowe syndrome.
31674016 Ye et al. (2020) did a multicenter genotype and phenotype study of Chinese children with Dent disease, which recruited 45 pediatric probands from 45 families from 12 different regions of China recruited from 2014 to 2018. Besides variants in CLCN5 (Dent disease type 1), they described 13 variants of OCRL gene, including 4 frame shift variants, in 13 families with Dent disease type 2.

Haploinsufficiency phenotype comments:

Loss of function variants in OCRL gene in males are associated with both the Lowe oculocerebrorenal syndrome, a multisystemic disease and Dent-2 disease, a renal tubulopathy. The genotype-phenotype correlations between the two conditions are not well understood. It is believed that loss of function variants in exons 1-7 are more often associated with Dent disease, while variants in exons 8-23 are more often associated with Lowe syndrome (see GeneReviews for further information). Hundreds of variants have been identified so far, and majority are identified in patients with Lowe syndrome. Up to 60% are truncating variants. In Lowe syndrome, nearly all postpubertal carrier females may have characteristic findings in the lens of the eye on slit lamp examination. Also, affected females with the clinical manifestations of Lowe syndrome have been reported (J Hum Genet. 2006;51(11):1030-1036. PMID: 16955230). In Dent 2 disease, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely develop 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.