ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000005.9) (NC_000005.10)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
16718694 A GABRA1 truncating mutation was detected in a patient with childhood absence epilepsy. Functional studies showed no detectable GABA-evoked currents for the mutant, truncated receptor, which was not integrated into the surface membrane. The authors concluded that this de novo mutation caused childhood epilepsy through loss of function and haploinsufficiency of the GABA(A) receptor alpha(1)-subunit.
21714819 Authors detected a K353delins18X mutation in a French Canadian family with idiopathic generalized epilepsy. Carriers had late-onset afebrile, generalized tonic-clonic seizures, as well as photosensitivity. However, one family member, an obligate carrier, was unaffected.
22812724 Heterozygous knock-out mouse model cause reduced viability and absence-llike seizures in the mouse. SWDs (Spike wave discharges) appeared to be sex dependent with more occurring in females than males. The authors suggest haploinsufficiency as a major mechanism associated with GABRA1-dependent epilepsy.

Haploinsufficiency phenotype comments:

Heterozygous GABRA1 mutations are associated with autosomal dominant susceptibility to childhood onset epilepsy. The cumulative evidence from family, functional and mouse studies is supportive of haploinsufficency of this gene as a mechanism for disease. Due to lack of published cases of full or partial gene deletions, the score of 2 is given at this time.

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