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Mutations in the <jats:italic>RAF1<\/jats:italic> gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). <jats:italic>RAF1<\/jats:italic> mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C\u2010terminus. We present two boys with Noonan syndrome and the identical de novo <jats:italic>RAF1<\/jats:italic> missense variant c.1082G&gt;C\/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a <jats:italic>RAF1<\/jats:italic> allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial\u2010like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well\u2010established association of NS with malignant tumors, especially childhood hemato\u2010oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.38569","type":"journal-article","created":{"date-parts":[[2017,12,24]],"date-time":"2017-12-24T09:08:31Z","timestamp":1514106511000},"page":"470-476","source":"Crossref","is-referenced-by-count":20,"title":["The novel <i>RAF1<\/i> mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor"],"prefix":"10.1002","volume":"176","author":[{"given":"Frederike L.","family":"Harms","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University Medical Center Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malik","family":"Alawi","sequence":"additional","affiliation":[{"name":"University 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