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Genet Med. 2018 Nov;20(11):1334-1345. doi: 10.1038/gim.2018.3. Epub 2018 Mar 1.

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

Author information

1
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
Département de Génétique, Hôpital Robert Debré and Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France.
3
Icahn School of Medicine at Mount Sinai, Molecular Genetic Testing Laboratory, New York, New York, USA.
4
Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, USA.
5
Greenwood Genetic Center, Greenwood, South Carolina, USA.
6
Laboratory for Molecular Medicine, Partners Healthcare, Cambridge, Massachusetts, USA.
7
Department of Pediatrics, University of California Davis, UC Davis MIND Institute, Sacramento, California, USA.
8
GeneDx, Gaithersburg, Maryland, USA.
9
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
10
GeneDx, Gaithersburg, Maryland, USA. lvincent@genedx.com.

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 Unpublished case-level data from participating laboratories impacted 45% of classifications supporting the need for data sharing.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

KEYWORDS:

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

PMID:
29493581
PMCID:
PMC6119537
DOI:
10.1038/gim.2018.3
[Indexed for MEDLINE]
Free PMC Article

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