{Reference Type}: Journal Article
{Title}: ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.
{Author}: Gelb BD;Cavé H;Dillon MW;Gripp KW;Lee JA;Mason-Suares H;Rauen KA;Williams B;Zenker M;Vincent LM; ;
{Journal}: Genet Med
{Volume}: 20
{Issue}: 11
{Year}: 11 2018
{Factor}: 8.864
{DOI}: 10.1038/gim.2018.3
{Abstract}: 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.<BR>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.<BR>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 Unpublished case-level data from participating laboratories impacted 45% of classifications supporting the need for data sharing.<BR>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.