Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels
Year: 2025
Type: article
Abstract: Purpose: The ClinGen RASopathy (RAS) Variant Curation Expert Panel (VCEP) previously established RASopathy specifications to the American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) variant classification framework for more consistent and accurate variant classification. Advances in the understanding of RASopathies and new clinical genetic testing algorithms required updated specifications. Methods: The RAS Gene Curation Expert Panel recurated 6 gene-disease relationships, and the RAS VCEP evaluated the previous specifications to develop updated RASopathy specifications for the ACMG/AMP framework. The performance of these updated specifications was tested by reassessing 59 previously classified variants and 88 new pilot variants. Results: Five gene-disease relationships were upgraded to Definitive, whereas 1 was upgraded to Moderate. Updated specifications were applied to 11 ACMG/AMP criteria for disorders with a dominant inheritance, 3 criteria for recessive inheritance, and 4 criteria to align with recommendations from the ClinGen Sequence Variant Interpretation Working Group. Assessment of variants demonstrated no major shifts in classifications compared with previous RAS VCEP or ClinVar classifications. Conclusion: Updated RASopathy specifications improve the classification of variants associated with recessive disease and observed in exome/genome cases. Most of these specifications may also be used as a baseline for other rare Mendelian disorders.
Source: Genetics in Medicine Open
Authors: Emma H. Wilcox, Ryan F. Webb, Kezang C. Tshering, Madeline Y. Hughes, Hélène Cavé, Marina T. DiStefano, Hannah Dziadzio, Kate Garber, Bruce D. Gelb, Karen W. Gripp, Shoji Ichikawa, Jennifer A. Lee, Hannah McCurry, Marco Tartaglia, Bradley Williams, Martin Zenker, Lisa M. Vincent, Heather Mason-Suares, Bradley Williams, Bruce Gelb, Hannah Dziadzio, Heather Mason-Suares, Hélène Cavé, Jennifer Lee, Karen Gripp, Kat Lafferty, Kezang Tshering, Lisa Vincent, Luis Enrique Gomez, Marco Tartaglia, Marina DiStefano, Martin Zenker, Reza Ahmadian, Ryan Webb, Shoji Ichikawa
Institutions: Broad Institute, Brown University, Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Hôpital Robert-Debré, Emory University, Icahn School of Medicine at Mount Sinai, Ambry Genetics (United States), Greenwood Genetic Center, Bambino Gesù Children's Hospital, University Hospital Magdeburg, Natera (United States), Mass General Brigham
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,200
Funders: European Commission, Bundesministerium für Bildung und Forschung, Ministero della Salute, Associazione Italiana per la Ricerca sul Cancro, National Human Genome Research Institute, National Eye Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Expert curation of clinically significant variants in genes for early onset retinal degeneration, G2921227375, G325310976, ClinGen Expert Curation Panel for Severe Structural Anomalies and Stillbirth, G3984118416, The Clinical Genome Resource - Expert Curation and EHR Integration, Congenital Heart Disease Expert Curation Panel, Clinical Genome Resource, Gene Curation Expert Panel for Syndromic Disorders, InSiGHT-ClinGen Polyposis/Colon Cancer Variant Curation Expert Panel, Genomic Expert Curation Panels for Pediatric Malignancies, G6993661028, Primary Mitochondrial Disease Expert Curation Panel, Comprehensive gene and DNA variant curation for neuromuscular diseases, Clinical Genome Resource (ClinGen), Broad-Geisinger Clinical Genome Resource, Myeloid Malignancy Variant Curation Expert Panel, ClinGen Expert Curation Panel for the Epilepsies, Expert curation of sequence variants in the proximal urea cycle genes, Curation Expert Panels for BRCA1/2 and Hereditary Breast, Ovarian and Pancreatic (HBOP) Cancer Genes, Curation of genetic defects causing combined immunodeficiency and infections in children, Integrative Curation of Clinically Relevant Variants in X-Linked Inherited Retinal Disease Genes
OpenAlex ID: W4409537404