Only two patients to date have been identified to have a cardiofaciocutaneous syndrome (CFC) diagnosis with NRAS variants (Altmuller et al., 2017). Of note, one patient had a complex phenotype that may be due to modifications from a 22q11.23 rearrangement, and the other patient presented with a p.T50I variant which has also been identified in patients with Noonan syndrome (NS) and no or mild developmental problems. This 11-year-old individual was noted to have mildly delayed motor and intellectual development with CFC facial features; however, variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of NS versus CFC. The NRAS gene is also located in the Ras/MAPK pathway, which is associated with the CFC phenotype (Aoki et al., 2016; Rauen, 2013). In summary, the evidence supporting the association between NRAS and CFC is Limited at this time. Of note, NRAS has also been classified as Definitive in association with NS and as Limited in association with NS with multiple lentigines and Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating NRAS 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).
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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