NR2F2 was first reported in relation to autosomal dominant multiple congenital anomalies/dysmorphic syndrome-NR2F2 in 2014 (Al Turk et al., PMID:24702954). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, and phenotypic variability. Therefore, the following disease entities have been split into separate entities: 46XX sex reversal 5 (OMIM:618901), Congenital heart defects, multiple types, 4 (OMIM: 615779). Nine unique variants (missense, nonsense, frameshift, splice acceptor) and seven of which were de novo that have been reported in ten probands in five publications (PMIDs: 24702954, 27363585, 29663647, 29222010, 37500725) are included in this curation.Two of the variants were found to segregated respectively in two separate families (PMID:24702954, 29222010). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by a mouse model, and expression data (PMIDs: 10215630, 24702954). In summary, NR2F2 is definitively associated with autosomal dominant multiple congenital anomalies/dysmorphic syndrome-NR2F2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 8/1/2023 (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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