ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)

Haploinsufficiency phenotype comments:

Familial hyperinsulinemia ( can be caused by homozygous loss of function mutations in ABCC8 and is typically diffuse pancreatic disease. A subset of cases are caused by paternally inherited heterozygous mutations that lead to focal disease due to somatic loss of heterozygosity, with penetrance of 1-2%. Loss of heterozygosity results in expression of this AR condition in a histologically focal manner. Flanagan (2011, PMID:21978130) reports 2 individuals with focal hyperinsulinemia with paternally inherited partial gene deletions. Affected pancreatic tissue was not available for confirmation of loss of heterozygosity. Damaj (2008, PMID: 18796520) reports 1 individual with focal hyperinsulinemia cause by a paternally inherited 5 basepair deletion in ABCC8 and subsequent somatic paternal isodisomy and loss of heterozygosity. Bellanne-Chantelot (2010, PMID:20685672) reports a large study of 37patients with focal hyperinsulinemia and review of previous studies. Multiple frameshift or truncating heterozygou mutations are reported. Of cases with complete parental information, 2 were de novo and the rest were paternal. Loss of heterozygosity in the affected tissue was documented for two patients. Permanent neonatal diabetes mellitus ( can be caused by activating missense mutations in ABCC8 (with both dominant and recessive inheritance). Mutations lead to decreased sensitivity to channel inhibitors and subsequent increased cellular activity (Babenko, PMID: 16885549). Expression is variable and can include childhood or adult onset diabetes.

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