ClinGen Dosage Sensitivity Curation Page

GJA1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000006.11) (NC_000006.12)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
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Haploinsufficiency phenotype comments:

Mutations in the GJA1 gene (OMIM: 121014) have been identified in several clinically and genetically heterogeneous groups of autosomal dominant and recessive diseases: Syndactyly, type III (OMIM: 186100), Oculodentodigital dysplasia, autosomal recessive (OMIM: 257850), Oculodentodigital dysplasia, autosomal dominant (ODDD-AD, OMIM: 164200), Hypoplastic left heart syndrome 1 (OMIM: 241550), Hallermann-Streiff syndrome (OMIM: 234100) and Atrioventricular septal defect 3 (OMIM: 600309). The GJA1gene product, connexin 43, is a transmembrane protein that assembles in groups of six (hemichannels) involved in the formation of gap junctions. In 2003, Paznekas et al, (PMID: 12457340), identified 16 missense mutations and one codon duplication in 12 familial and 5 sporadic cases of ODDD. To date, more than 65 known mutations within the coding sequence of the GJA1 gene have been identified (summarized in Paznekas et al, PMID: 19338053 and Huang et al. PMID: 23606748). The majority of mutations (85%) have been missense mutations with the remaining mutations being codon duplications and deletions as well as frameshift mutations. The identified frameshift mutations occur in the latter portion of the coding regions and are believed to also generate truncated dominant negative or a gain of function connexin 43 protein products (Gong et al, 2006. PMID: 16891658). In addition, an autosomal recessive homozygous truncating mutation (p.R33X) was identified as being inherited from heterozygous unaffected parents (Richardson et al, PubMed: 16816024). The observation that the majority of identified mutations are missense mutations, together with the rarity of deletions or truncating mutations, suggests that either a dominant negative or a gain of function mechanism. There is no evidence to suggest that loss of a single copy of GJA1 causes an abnormal phenotype. Variation in GJA1 was reported in individuals with nonsyndromic hearing loss; however, the overall evidence that GJA1, when altered, causes nonsyndromic hearing loss was expert reviewed by the ClinGen Hearing Loss Working Group and classified as DISPUTED.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
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Triplosensitivity phenotype comment:

There is no evidence to suggest that gain of a single copy of GJA1 causes an abnormal phenotype.