ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21326233 Charizopoulou et al. 2011 identified a c.903G>A p.Trp301X variant segregating with progressive sensorineural hearing impairment in 2 affected and 1 unaffected sibling from a consanguineous marriage. This variant is in the last exon and only removes 12/313 AA from the protein, however it still implies an autosomal recessive inheritance pattern. This study also identified another family with 3 affected p.Leu262Arg homozygous and 2 unaffected without the genotype. This variant was also tested in a mouse model that exhibited progressive hearig loss and susceptibility to juvenile audiogenic seizures. They were able to rescue hearing loss and juvenile seizure phenotype via transgenic expression of the Gipc3 gene. Therefore, this study demonstrates two different variants supporting an autosomal recessive mechanism of the progressive hearing loss phenotype.
21660509 Rehman et al identified 7 families with severe-profound sensorineural hearing loss segregating with homozygous variants in consanguineous families. There were 6 families that had missense variants and one family that had a frameshift variant that causes a stop codon in the penultimate exon (further than 50 bp away). Though these variants do not have functional evidence to support their effects, they were all shown to segregate in large families with disease, see figure 2a. The inheritance is autosomal recessive and does not support haploinsufficiency as a mechanism of disease.

Haploinsufficiency phenotype comments:

There are several large families with autosomal recessive (AR) progressive, severe-profound nonsyndromic (NS) sensorineural hearing loss (HL) published in Charizpoulou et al. 2011 and Rehman et al. 2011. There is more genetic evidence available, but between these two publications there are 9 families with 7 missense and 2 loss of function variants cosegregating with disease. Additionally, there is a mouse model transfected with the c.343G>A missense variant that demonstrated hearing loss as well as audiogenic seizures that was rescued by transgenic Gipc3 expression. This same mouse model was found by Ohn et al. 2016 to have Ca2+ influx and gradients affected resulting in a hyperpolarizing shift in the activation that may be causing the phenotype. In summary, there is sufficient funcitonal evidence to support that alterations to this gene cause hearing loss, and there is a great deal of evidence to support that the inheritance is autosomal recessive and that the hearing loss can range from mild-profound with a prelingual onset with progression. Furthermore, the overall evidence that GIPC3, when altered, causes ARNSHL has been expert reviewed by the ClinGen Hearing Loss Working Group and classified as DEFINITIVE

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

Triplosensitivity phenotype comment:

There is currently no evidence to support that gain of function of GIPC3 is a mechanism for disease.