AKT3 was FIRST reported in relation to overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes in 2012 (Poduri et al. 22500628). Several recurrent missense variants have been reported in humans (e.g. E17K) and also copy number gains have been associated with this phenotype, suggestive of a gain-of-function disease mechanism. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Experimental studies have been done on patient cell lines and non-patient derived cells that support this gain of function disease mechanism. In summary, AKT3 has been definitively associated with overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, and has been upheld over time. Of note this gene is part of a known 1q43q44 deletion syndrome and at least one AKT3 specific deletion has been reported in association with non-overgrowth disease. Therefore, loss-of-function variants in this gene may be associated with a different syndrome as well. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 05/25/2021 (SOP Version 7)
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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