Assessing the gene-disease association of 19 genes with the RASopathies using the ClinGen gene curation framework

Hum Mutat. 2018 Nov;39(11):1485-1493. doi: 10.1002/humu.23624.


The RASopathies are a complex group of conditions regarding phenotype and genetic etiology. The ClinGen RASopathy Expert Panel (RAS EP) assessed published and other publicly available evidence supporting the association of 19 genes with RASopathy conditions. Using the semiquantitative literature curation method developed by the ClinGen Gene Curation Working Group, evidence for each gene was curated and scored for Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome, NS with multiple lentigines, and Noonan-like syndrome with loose anagen hair. The curated evidence supporting each gene-disease relationship was then discussed and approved by the ClinGen RASopathy Expert Panel. Each association's strength was classified as definitive, strong, moderate, limited, disputed, or no evidence. Eleven genes were classified as definitively associated with at least one RASopathy condition. Two genes classified as strong for association with at least one RASopathy condition while one gene was moderate and three were limited. The RAS EP also disputed the association of two genes for all RASopathy conditions. Overall, our results provide a greater understanding of the different gene-disease relationships within the RASopathies and can help in guiding and directing clinicians, patients, and researchers who are identifying variants in individuals with a suspected RASopathy.

Keywords: ClinGen; RASopathy; gene curation; genetic; genomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Costello Syndrome / genetics
  • Ectodermal Dysplasia / genetics
  • Facies
  • Failure to Thrive / genetics
  • Heart Defects, Congenital / genetics
  • Humans
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology
  • Mutation / genetics
  • Noonan Syndrome / genetics
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • ras Proteins

Supplementary concepts

  • Cardiofaciocutaneous syndrome