There is a definitive association between alteration of the HRAS gene and a Costello syndrome (CS) phenotype. The maximum amount of scorable genetic evidence has been published showing de novo as well as non-de novo variants occur in HRAS in patients with CS (Alfieri et al., 2015; Aoki et al., 2005; Burkitt-Wright et al., 2012; Gripp et al., 2015; Hiippala et al., 2016; Lorenz et al., 2013; Xu, Wang, Lin, & Yu, 2015). Furthermore, the HRAS gene is the only gene that is definitively associated with CS (Rauen, 2007). The HRAS gene is also located in the Ras/MAPK pathway which is associated with the Costello phenotype (Aoki et al., 2016; Rauen, 2013). Finally, a mouse model with the p.Gly12Val variant in HRAS was found to possess CS specific features (Goodwin et al., 2014; Oba et al., 2018). Of note, HRAS has also been classified as disputed in association with Noonan syndrome (NS) with loose anagen hair. The ClinGen RASopathy Expert Panel found no evidence associating HRAS with NS, NS with multiple lentigines, or cardiofaciocutaneous syndrome. 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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