RRAS2 was first reported in relation to autosomal dominant Noonan syndrome (NS) in 2019 (Capri et al., PMID: 31130282; Niihori et al., PMID: 31130285). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, cardiofaciocutaneous syndrome, Costello syndrome, NS with loose anagen hair, or NS with multiple lentigines. No evidence was found to support these other RRAS2 gene-disease relationships. Seven variants (missense and in-frame insertion/duplication) that have been reported in 9 probands in 4 publications (PMIDs: 31130282, 31130285, 33686258, 34648682) are included in this curation. The mechanism of pathogenicity is known to be GOF. This gene-disease association is also supported by a zebrafish model that displayed features that may be indicative of a RASopathy. RRAS2 shares downstream effectors with the other members of the RAS subfamily, however, little information exists about the function of the protein in the cellular processes and development. Variant level experimental evidence exploring the intracellular signaling pathways affected in NS has been done (PMIDs: 31130282). In summary, there is definitive evidence to support the relationship between RRAS2 and autosomal dominant Noonan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the RASopathy GCEP on 6/27/2019. It was reevaluated on 12/14/2022 (SOP version 9). As a result of this reevaluation, the classification did change from Strong to Definitive due to replication over time and more evidence being published.
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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