The POLR2A gene, encoding the largest subunit of RNA Pol II, was first reported in relation to autosomal dominant neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities in 2019 (Haijes et. al., PMID 31353023). The original curation contained 15 unique de novo missense or loss-of-function variants from a single publication (PMID:31353023). As a result of this re-evaluation, an additional 2 variants are included in the curation from a second publication (PMID: 33665635). More genetic evidence is available in the literature. The reported mechanism of disease for POLR2A variants range from mild haploinsufficiency to severe dominant-negative depending on variant location and consequence. This gene-disease relationship is supported by in vitro functional assays in yeast and HeLa cells showing reduced cell viability with specific patient variants (PMID 31353023). The gene-disease pair was originally evaluated by the Syndromic Disorders GCEP on August 5th, 2020 and was re-evaluated on March 15th, 2024. As a result of this re-evaluation, the classification increased from Moderate to Definitive with the addition of new published case reports (PMIDs: 33665635). This gene-disease relationship has now been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on March 15th, 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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