ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
15024691 Toomes et al., (2004) identified six different heterozygous sequence-level LRP5 mutations (3 nonsense and 3 missense) in six unrelated families with Familial Exudative Vitreoretinopathy (FEVR), characterized by the incomplete development of the retinal vasculature and visual impairments that range from mild vision loss to blindness. The FEVR phenotype may result in no overt clinical phenotype, and may only be detected by fluorescein angiography. For two families, nonsense mutations segregated with FEVR in all patients tested; a different nonsense mutation showed incomplete penetrance and for two patients with missense mutations, the same alteration was identified in an unaffected parent. Of note, these apparently non-penetrant individuals were not evaluated by fluorescein angiography. The missense mutations were not found in 200 ethnically matched control individuals. Functional/expression studies were not performed; however, these alleles are predicted to result in a loss-of-function.
20340138 Nikopoulos et al. 2010 report a novel nonsense variant (p.W993X) in a sporadic patient with FEVR. The authors do not comment on the inheritance of this variant. Two other novel missense and a novel splice site variant are reported in this study.

Haploinsufficiency phenotype comments:

LRP5 is a low-density-lipoprotein receptor-related protein that regulates bone formation and maintenance and vascularization in the eye (Dong et al. 1998, Kato et al. 2002). Heterozygous sequence-level mutations and intragenic deletions in LRP5 have been identified in association with familial exudative vitreorentinopathy (FEVR), a hereditary visual impariment disorder, and in obligate carriers of autosomal recessive osteoporosis-pseudoglioma syndrome (OPPG) mutations, who have have reduced bone mineral density phenotypes. FEVR associated with LRP5 variants can be inherited in both autosomal dominant and autosomal recessive manners. Many LRP5 mutations are predicted to result in a loss-of-function, however corresponding functional data are lacking and as yet, whole LRP5 gene deletion has not been reported. Furthermore, not all carriers of LRP5 mutations exhibit these phenotypes. With consideration for this information, the current evidence in support of haploinsufficiency for this gene is considered to be emerging and the haploinsufficiency score is a 2.

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

Triplosensitivity phenotype comment:

At this time there is not evidence to support triplosensitivity