RASopathies

The autosomal dominant RASopathies are a group of phenotypically related developmental disorders that result from gain-of-function pathogenic variants in genes of the Ras/MAPK pathway. These fully penetrant disorders can present with variable expressivity and severity even among patients with the same pathogenic variant. Therefore, a molecular diagnosis crucial to supporting a clinical diagnosis of these disorders. Classifying variants in RASopathy genes commonly utilize only a particular subset of ACMG-AMP criteria. Key evidence for classifications include minor allele frequencies in the general population, number of affected individuals, segregation in affected family members, and de novo occurrences of the variant. This chapter illustrates how to use and adjust the strength of ACMG-AMP criteria to provide accurate and uniform classifications of variants observed in association with the RASopathies.