ATE1 was first reported in relation to autosomal recessive congenital heart disease in 2016 (Priest et al., PMID: 27058611). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, atrioventricular septal defect and congenital heart disease have been lumped into one disease entity. Two unique variants, a missense and a CNV, have been reported in two probands in two publications (PMIDs: 27058611, 31552105). However, the missense variant had a high minor allele frequency (> 0.00001) in gnomAD v2.1.1 and a very low REVEL score, and was, therefore, not scored. The gene-disease relationship is supported by a knockout mouse model and functional alteration data (PMIDs: 12098698, 16222293, 16794040). Although there is sufficient experimental evidence, the genetic evidence is not convincing enough to support the relationship. In summary, the evidence supporting the relationship between ATE1 and autosomal recessive congenital heart diseases has been disputed, and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role ATE1 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 8/14/2023 (SOP Version 9).
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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