GJA5 was first reported in relation to autosomal dominant congenital heart disease in 2004 (Christiansen et al PMID 15117819) when 3 deletions were identified on chromosome 1q21.1 which included GJA5 as well as several other genes. There have been multiple publications demonstrating deletions and duplications of 1q21.1 in patients with congenital heart disease (PMID 15117819, 19597493, 22318994, 22939634, 24021551, 26279651, 28905115, 35045913). A recurrent missense variant was identified in two patients with tetralogy of Fallot but the maximum allele frequency was above the allele frequency threshold of 1x10-5 so these variants were not scored. This gene disease relationship is supported by expression studies, a mouse model with congenital heart defects, protein interaction data, (PMIDs 9285645, 12842919, 15537493). In summary, the evidence supporting the relationship between GJA5 and autosomal dominant congenital heart disease has been disputed due to the lack of human genetic evidence and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role GJA5 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 4/2/2024 (SOP version 10)
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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