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ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000005.9) (NC_000005.10)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
12117362 Kananura et al. (2002): A total of 135 patients and 154 unrelated, ethnically matched controls were screened for mutations in GABRG2. An IVS6 + 2T-->G point mutation (HGVS c.769+2T>G) was found to cosegregate with the disease status in a family with childhood absence epilepsy and febrile convulsions. The mutation was predicted to produce a non-functional protein.
19261880 Kang et al. (2009): A family with generalized epilepsy and febrile seizures was found to have a mutation that introduces a premature stop codon at Q351 (exon 9) of GABRB2. However, whether the mechanism was loss-of-function or a dominant negative effect, or a combination of both is not yet clear, at least for mutations in the 3' of the gene.
24480790 Ishii et al. (2014): A heterozygous nonsense mutation (c.118C>T, p.Q40X) in GABRG2 was identified in dizygotic twin girls with Dravet syndrome and their apparently healthy father. The authors concluded that the phenotype was due to a dominant negative effect. This is at odds with an earlier publication (Huang et al., 2012 PMID 22750526], which found that the mutation was subject to nonsense mediated mRNA decay.

Haploinsufficiency phenotype comments:

Missense, splice and nonsense mutations in GABRG2 are associated with Dravet syndrome and idiopathic generalized epilepsy. The majority of mutations, nonsense and splice included, appear to have a dominant negative effect, causing severe epilepsy. However, some nonsense mutations are thought to result in haploinsufficiency, and these may be associated with a milder epilepsy phenotype (Kang and Macdonald, 2016 PMID:27367160 ).

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