Dataset Information

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 (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 Unpublished case-level data from participating laboratories impacted 45% of classifications supporting the need for data sharing.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.

SUBMITTER: Gelb BD

PROVIDER: S-EPMC6119537 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.

Gelb Bruce D BD Cavé Hélène H Dillon Mitchell W MW Gripp Karen W KW Lee Jennifer A JA Mason-Suares Heather H Rauen Katherine A KA Williams Bradley B Zenker Martin M Vincent Lisa M LM

Genetics in medicine : official journal of the American College of Medical Genetics 20180301 11

<h4>Purpose</h4>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 classificati ...[more]

PMID: 29493581

Similar Datasets

Project description:Social cognition, the perception and processing of social information, is adversely affected in multiple psychiatric, neurological, and neurodevelopmental disorders, and these impairments negatively impact quality of life for individuals across the globe. Despite the clear importance of social cognition, efforts to advance research via harmonization of data across cultures and diagnoses has been stymied by the lack of uniformly used and suitable assessments. To address this issue, the current study conducted an expert survey and consensus process to identify social cognitive assessments that are best suited for cross-cultural and transdiagnostic use among adults. A large group of experts in social cognition were surveyed to gather nominations for cross-culturally and transdiagnostically appropriate measures. These measures were then critically evaluated by a smaller group of experts using a Delphi consensus process to identify the best existing tasks for each use. Ninety-eight experts, representing 25 countries, responded to the initial survey and nominated a total of 81 tasks. Initial rounds of the Delphi process identified 50 tasks with adequate psychometric properties that were then subdivided into social cognition domains. For each domain, members ranked the five best tasks, once for cross-cultural use and once for transdiagnostic use, and rated the suitability of those tasks for the intended use. No tasks were identified as ideally suited for either use; however, within each domain, 4-5 tasks emerged as the most consistently selected, and all were ranked as having "good" or better suitability for use. While there is still a critical need for social cognitive assessments that are specifically designed for cross-cultural and transdiagnostic use, there does appear to be a handful of existing tasks that are currently available and likely informative. Caution is warranted however, as these still require comprehensive evaluation in cross-cultural and transdiagnostic studies.

Dataset Information

ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.

Purpose

Methods

Results

Conclusion

Publications

ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets