ClinGen’s RASopathy Expert Panel consensus methods for variant interpretation

for the ClinGen RASopathy Working Group

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


Purpose: Standardized and accurate variant assessment is essential for effective medical care. To that end, Clinical Genome (ClinGen) Resource clinical domain working groups (CDWGs) are systematically reviewing disease-associated genes for sufficient evidence to support disease causality and creating disease-specific specifications of American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines for consistent and accurate variant classification. Methods: The ClinGen RASopathy CDWG established an expert panel to curate gene information and generate gene- and disease-specific specifications to ACMG-AMP variant classification framework. These specifications were tested by classifying 37 exemplar pathogenic variants plus an additional 66 variants in ClinVar distributed across nine RASopathy genes. Results: RASopathy-related specifications were applied to 16 ACMG-AMP criteria, with 5 also having adjustable strength with availability of additional evidence. Another 5 criteria were deemed not applicable. Key adjustments to minor allele frequency thresholds, multiple de novo occurrence events and/or segregation, and strength adjustments impacted 60% of variant classifications. Unpublished case-level data from participating laboratories impacted 45% of classifications supporting the need for data sharing. Conclusion: RAS-specific ACMG-AMP specifications optimized the utility of available clinical evidence and Ras/MAPK pathway–specific characteristics to consistently classify RASopathy-associated variants. These specifications highlight how grouping genes by shared features promotes rapid multigenic variant assessment without sacrificing specificity and accuracy.

Original languageEnglish
Pages (from-to)1334-1345
Number of pages12
JournalGenetics in Medicine
Issue number11
StatePublished - 1 Nov 2018


  • ClinGen
  • Noonan
  • RASopathy
  • Ras/MAPK
  • variant interpretation


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