PIK3R2 was first reported in relation to autosomal dominant overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes in 2012 (Riviere et al., PMID: 22729224). At least 4 unique de novo missense variants have been reported in humans. Evidence supporting this gene-disease relationship including case-level data, case-control data, and experimental data. Variants in this gene have been reported in at least 35 probands in at least 4 publications (PMIDs: 22729224, 26520804, 26860062, 23745724) with the vast majority of cases accounted for by recurrent a c.1117G>A (p.G373R) mutation (PMID: 26520804). More evidence is available in the literature, but the maximal score for genetic evidence (12 pts) has been reached. The mechanism of disease is heterozygous gain of function (PMID: 28086757). This gene-disease relationship is supported by cell culture assays using patient derived cells. In summary, PIK3R2 is definitively associated with autosomal dominant overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and it has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 3/23/2021 (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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