ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
  • Haploinsufficiency score: Gene associated with autosomal recessive phenotype
  • Strength of Evidence (disclaimer): Gene associated with autosomal recessive phenotype

Haploinsufficiency phenotype comments:

Homozygous/compound heterozygous variants cause bile salt export pump (BSEP) deficiency, with severe deficiency categorized as progressive familial intrahepatic cholestasis. Strautnieks et al (PMID 18395098) described 82 different ABCB11 variants in 109 familes, including 9 nonsense, 10 small insertions/deletions, 15 splice site, 3 whole-gene deletions, and 45 missesnse changes. Fifteen percent (19/128) developed hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC). Correlation with genotype identified those with 2 loss of function (LOF) variants being at particular risk, with thirty-eight percent (8/21) with 2 predicted LOF variants developing malignancy versus 10% of patients (11/107) with potentially less severe defects, giving a relative risk of 3.7 (confidence limits, 1.7? 8.1; P = .003). Only one individual with 1 splice site (c.908+1G>T) and NO second variant detected, who developed HCC (same as IVS9+1G>T from PMID; 16871584). While biallelic LOF variants appear to lead to a greater phenotype, currently no evidence of phenotype in carriers due to haploinsufficiency.

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

Triplosensitivity phenotype comment:

no evidence for triplosensitivity