Submission Details

There have been three studies published implicating NRAS with Noonan syndrome with multiple lentigines (NSML), however only one unique variant has been identified. The p.Gly60Glu variant has been identified in de novo cases, segregated in one family with disease, and individuals with unknown origin who possess clinical features of NSML (Ekvall et al., 2015; Kraoua et al., 2012). This variant has also been found in individuals without multiple lentigines with clinical features of NS (Cirstea et al., 2010). Of note, one individual with the p.Gly13Asp variant possessed the juvenile myelomonocytic leukemia phenotype in addition to clinical features of NSML (De Filippi et al., 2009). This case was not scored, but should be noted as a possible additional phenotype. The NRAS gene is also located in the Ras/MAPK pathway, which is associated with the NSML phenotype (Aoki et al., 2016; Rauen, 2013). In summary, the evidence supporting NRAS’s association with NSML is Limited, however the presence of multiple lentigines makes this evidence distinct from the other Noonan cases. Of note, NRAS has also been classified as Definitive in association with NS and as Limited in association with Costello syndrome and cardiofaciocutaneous 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 5/30/18 (SOP Version 5).