Submission Details

RAF1 was first reported in relation to autosomal dominant Noonan syndrome in 2007 (Pandit et al., PMID: 17603483; Razzaque et al., PMID:17603482). The RAF1 gene is located in the Ras/MAPK pathway, which is associated with the NS phenotype and variants in this gene found in patients disrupt the RAS pathway function. Of note, RAF1 is also classified as Limited in association with NS with multiple lentigines and as Disputed in association with Costello syndrome and cardiofaciocutaneous syndrome. The GCEP found no evidence associating RAF1 with NS-like disorder with loose anagen hair. The typical prenatal Noonan presentation includes increased nuchal translucency/nuchal fold, which is seen in the first trimester and may persist throughout later stages of the prenatal course, as well as other lymphatic anomalies (pleural and pericardial effusion, ascites, fetal hydrops). Hypertrophic cardiomyopathy, hydronephrosis, short long bones, and various brain abnormalities may be observed. Other prenatal manifestations may include (progressive) polyhydramnios, absence of the ductus venosis and possible intrauterine fetal demise (PMIDs: 22821648, 26467173, 28777121, 30359267, 29907801, 36155125, 35278234). Nine unique variants (missense and deletion) that have been reported in 21 probands in 13 publications (PMIDs: 17603483, 17603482, 25706034, 23877478, 23613113, 22821648, 20052757, 26467173, 28777121, 29907801, 30359267, 36155125, 35278234) are included in this curation. The maximum amount of scores for genetic evidence has been reached. This gene-disease relationship is supported by a protein interaction study showing RAF1 as an established gene in the RAS/MAPK pathway and a mouse model replicating the human disease (PMIDs: 23613113, 21339642). In summary, there is definitive evidence to support the relationship between RAF1 and autosomal dominant Noonan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Rasopathies GCEP on 7/24/18 as per SOP v5. It was reevaluated in 2024 using SOP v10 to include prenatal Noonan cases. As a result of this reevaluation, this record underwent an update in scoring to be consistent with SOP v10. New case level evidence has been added, and the classification remained the same (PMIDs: 26467173, 28777121, 30359267, 29907801, 36155125, 35278234). This classification was approved by the ClinGen RASopathies GCEP on the meeting date October 23rd, 2024 (SOP Version 10).

RAF1 was first reported in relation to autosomal dominant Noonan syndrome in 2007 (Pandit et al., PMID: 17603483; Razzaque et al., PMID:17603482). The RAF1 gene is located in the Ras/MAPK pathway, which is associated with the NS phenotype and variants in this gene found in patients disrupt the RAS pathway function. Of note, RAF1 is also classified as Limited in association with NS with multiple lentigines and as Disputed in association with Costello syndrome and cardiofaciocutaneous syndrome. The GCEP found no evidence associating RAF1 with NS-like disorder with loose anagen hair. The typical prenatal Noonan presentation includes fetal hydrops, lymphatic anomalies (pleural and pericardial effusion, ascites), hydronephrosis, increased nuchal translucency/nuchal fold, which is seen in the first trimester and persists throughout later stages of the prenatal course. Hypertrophic cardiomyopathy, short long bones, and various brain abnormalities may be observed. Other prenatal manifestations may include (progressive) polyhydramnios, a single umbilical artery, and possible intrauterine fetal demise (PMIDs: 22821648, 26467173, 28777121, 30359267, 29907801, 36155125, 35278234). Nine unique variants (missense and deletion) that have been reported in 21 probands in 13 publications (PMIDs: 17603483, 17603482, 25706034, 23877478, 23613113, 22821648, 20052757, 26467173, 28777121, 29907801, 30359267, 36155125, 35278234) are included in this curation. The maximum amount of scores for genetic evidence has been reached. This gene-disease relationship is supported by a protein interaction study showing RAF1 as an established gene in the RAS/MAPK pathway and a mouse model replicating the human disease (PMIDs: 23613113, 21339642). In summary, there is definitive evidence to support the relationship between RAF1 and autosomal dominant Noonan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Rasopathies GCEP on 7/24/18 as per SOP v5. It was reevaluated in 2024 using SOP v10 to include prenatal Noonan cases. As a result of this reevaluation, this record underwent an update in scoring to be consistent with SOP v10. New case level evidence has been added, and the classification remained the same (PMIDs: 26467173, 28777121, 30359267, 29907801, 36155125, 35278234). This classification was approved by the ClinGen RASopathies GCEP on the meeting date [TBD] (SOP Version 10).