The maximum amount of scorable genetic evidence has been published showing de novo as well as non-de novo variants occur in KRAS in patients with cardiofaciocutaneous (CFC) syndrome (Adachi, Abe, Aoki, & Matsubara, 2012; Nava et al., 2007; Niihori et al., 2006; Nystrom et al., 2008; Sovik et al., 2007; Zenker et al., 2007). However, variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of Noonan syndrome (NS) versus CFC. Furthermore, there is sufficient variant overlap between KRAS-associated Noonan and CFC phenotypes. Additional genotype-phenotype correlations are necessary to solidify the association of KRAS with CFC syndrome, therefore it cannot yet be classified as Definitive. The KRAS gene is also located in the Ras/MAPK pathway, which is associated with the CFC phenotype (Aoki et al., 2016; Rauen, 2013). Of note, KRAS has also been classified as Definitive in association with Noonan syndrome and as Disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating KRAS with NS-like disorder with loose anagen hair or NS with multiple lentigines. In summary, the evidence supporting the association between KRAS and CFC is Strong. 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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