ClinGen Dosage Sensitivity Curation Page

ACVRL1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000012.11) (NC_000012.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
18312453 Shoukier et al (2008) documented two cases in which large deletions encompassing the entire ACVRL1 gene cause hemorrhagic telangiectasia
20414677 Richards-Yutz et al 2010 provided a review of the molecular diagnosis of HHT in a series of 600 individuals. Approximately one third of pathogenic variants in ACVRL1 are functionally null alleles.

Haploinsufficiency phenotype comments:

ACVRL1 encodes Activin A receptor, type II-like kinase 1, a cell-surface receptor for the TGF-beta superfamily of ligands that functions in endothelial tissues to regulate signal transduction during vascular morphogenesis. Pathogenic variants in the ACVRL1 gene cause autosomal dominant hereditary hemorrhagic telangiectasia (HHT), a vascular malformation disorder characterized clinically by recurrent epistaxis (nosebleeds), cutaneous or mucosal telangiectases, and visceral arteriovenous malformations that may lead to symptoms when they occur in the brain, liver, or lungs. Age of onset for HHT symptoms is generally in adolescence or adulthood, although cases of early, severe onset have been reported (see GeneReviews). It is suspected due to the possibility of late-onset HHT that this condition continues to be underdiagnosed. This likely contributes to the presence of individuals in population databases such as ExAC that harbor apparent loss-of-function ACVRL1 variants, although this gene is not thought to be loss-of-function tolerant. Genotype-phenotype correlation has not been well established for different classes of ACVRL1 variants, and extremely variable expressivity of HTT symptoms can be observed even within a family carrying the same pathogenic ACVRL1 variant. Most pathogenic ACVRL1 variants are sequence-level changes, although Shoukier et al. documented two cases in which large deletions encompassing the entire ACVRL1 gene cause HHT (Shoukier 2008). Approximately one third of pathogenic variants in ACVRL1 are functionally null alleles (Richards-Yutz et al 2010).

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