ClinGen’s RASopathy Expert Panel consensus methods for variant interpretation

Abstract

Purpose Standardized and accurate variant assessment is essential for effective medical care. To that end, Clinical Genome (ClinGen) Resource clinical domain working groups (CDWG) are systematically reviewing disease-associated genes for sufficient evidence to support disease causality and creating disease-specific specifications of ACMG-AMP guidelines for consistent and accurate variant classification. Methods The ClinGen RASopathy CDWG established an expert panel (EP) 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 sixteen ACMG-AMP criteria, with five also having adjustable strength with availability of additional evidence. Another five 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 Unpublished case-level data from participating laboratories impacted 45% of classifications supporting the need for data sharing. Conclusions 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 multi-genic variant assessment without sacrificing specificity and accuracy.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

“…Previous reports of single‐nucleotide variants were checked by consulting the Ensembl genome browser (http://www.ensembl.genome.org). The pathogenicity of variants was interpreted according to international expert consensus …”

Reclassification of the BRAF p.Ile208Val variant by case-level data sharing

“…Therefore, the presence of the variant in three individuals in the general population whose phenotypes are unavailable would not be sufficient evidence alone to rule out pathogenicity. However, we applied the ACMG/AMP BS2 rule per the RASopathy Expert Panel's specifications which asserts that the presence of a RASopathy variant in multiple healthy, phenotyped adult individuals is strong evidence that the variant is benign (Richards et al 2015; Gelb et al 2018). The p.Ile208Val variant has been observed in at least three phenotyped individuals without evidence of a RASopathy at the LMM and GeneDx.…”

“…The p.Ile208Val variant has been observed in at least three phenotyped individuals without evidence of a RASopathy at the LMM and GeneDx. The BS1 threshold for RASopathy variants is 0.025% (Gelb et al 2018), which is used as a strong piece of evidence toward benign when the frequency of the variant in the general population (i.e., gnomAD) is higher than this threshold. The RASopathy Expert Panel currently does not specify the use of less conservative allele frequency thresholds for strength lowering modifications to BS1.…”

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“…compared variant pathogenicity interpretations by several laboratories within the ClinGen frameworkGelb et al, 2018). These discrepancies may arise when variants have been assessed at different times, for different populations, and using different data types.…”