There have only been two individuals reported in published literature with RRAS variants and a Noonan syndrome (NS) phenotype (Flex et al., 2014). One individual was a de novo case, but the origin of the other patient’s variant was unknown. Therefore, the total genetic evidence available in the literature for this association was 2.5 points. In summary, there has only been limited evidence suggesting that RRAS alterations cause a RASopathy phenotype. Finally, the RRAS gene is also located in the Ras/MAPK pathway which is associated with the NS phenotype and variants found in NS patients in this gene disrupt the RAS pathway function as demonstrated by C. elegans models (Aoki et al., 2016; Flex et al., 2014; Rauen, 2013). Further evidence is needed to strengthen the clinical validity of the association between RRAS and NS. The ClinGen RASopathy Expert Panel found no evidence associating RRAS with cardiofaciocutaneous syndrome, Costello syndrome, NS with loose anagen hair or NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).
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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