Only 2 cases with RAF1 variants and a suspected Costello syndrome (CS) diagnosis have been published in the literature (Kobayashi et al., 2010). The authors state that they did not receive detailed clinical manifestations for one patient with a p.P261L variant of unknown origin and significance. The other case had a de novo p.N262K variant, but the patient died at 1 month of age and was not phenotyped directly by the authors. Both variants, p.P261L and p.N262K, were functionally assessed; however, due to lack of clinical manifestations obtained for these patients, this association is classified as Disputed. The HRAS gene is believed to be the only gene associated with CS (Aoki et al., 2005; Estep, Tidyman, Teitell, Cotter, & Rauen, 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007). Of note, RAF1 is also classified as Definitive in association with Noonan syndrome (NS), Limited in association with NS with multiple lentigines, and as Disputed in association with cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating RAF1 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).
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