ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000012.11) (NC_000012.12)

Haploinsufficiency phenotype comments:

Trudeau et al. (2006) report a 2?bp deletion in exon 24 in a 9?year old boy with mental retardation, pancerebellar atrophy, and ataxia. This change, Pro1719ArgfsX6, introduces a translation termination codon into the pore loop of domain 4, resulting in removal of the C?terminal cytoplasmic domain and predicted loss of channel function. The boy's mother, maternal aunt, and a male maternal first cousin were all found to have the same change; these individuals were not available for clinical examination, but reportedly had "emotional instability with mild cognitive impairment" (mother and maternal aunt) and attention deficit hyperactivity disorder (maternal first cousin). It is unknown whether any of these individuals had possible subclinical cerebellar atrophy. (PMID:16236810) Of note, Veeramah et al. (2012) (PMID: 22365152) report a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) identified on whole genome sequencing of a 15-year-old female proband with severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. Functional studies were reportedly consistent with a dominant gain-of-function phenotype. Given the lack of functional studies in the first paper and lack of clinical information regarding other family members with the variant, it is unclear if the clinical phenotype described is the result of haploinsufficiency of this gene, which is why it has been given a score of 0.

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