Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels
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 var...
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Elsevier
2025-01-01
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| Series: | Genetics in Medicine Open |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2949774425014694 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Emma H. Wilcox |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b78eaa9881a3495fa8c8d5da9e6a499c |
| institution | OA Journals |
| issn | 2949-7744 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Genetics in Medicine Open |
| spelling | doaj-art-b78eaa9881a3495fa8c8d5da9e6a499c2025-08-20T02:26:10ZengElsevierGenetics in Medicine Open2949-77442025-01-01310343010.1016/j.gimo.2025.103430Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panelsEmma H. Wilcox0Ryan F. Webb1Kezang C. Tshering2Madeline Y. Hughes3Hélène Cavé4Marina T. DiStefano5Hannah Dziadzio6Kate Garber7Bruce D. Gelb8Karen W. Gripp9Shoji Ichikawa10Jennifer A. Lee11Hannah McCurry12Marco Tartaglia13Bradley Williams14Martin Zenker15Lisa M. Vincent16Heather Mason-Suares17Bradley WilliamsBruce GelbHannah DziadzioHeather Mason-SuaresHélène CavéJennifer LeeKaren GrippKat LaffertyKezang TsheringLisa VincentLuis Enrique GomezMarco TartagliaMarina DiStefanoMartin ZenkerReza AhmadianRyan WebbShoji IchikawaMedical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA; The Warren Alpert Medical School of Brown University, Providence, RIMedical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MAMedical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MAMedical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MADépartement de Génétique, Hôpital Robert Debré (AP-HP), and Université Paris-Cité, Paris, FranceMedical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MAMedical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MADepartment of Human Genetics, Emory School of Medicine, Atlanta, GAMindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NYDivision of Medical Genetics, Nemours Children’s Hospital, Wilmington, DEAmbry Genetics, Aliso Viejo, CAGreenwood Genetic Center, Greenwood, SCMedical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MAOspedale Pediatrico Bambino Gesù, IRCCS, Rome, ItalyGeneDx, Gaithersburg, MDInstitute of Human Genetics, University Hospital Magdeburg, Magdeburg, GermanyNatera Inc, Austin, TXMass General Brigham, Laboratory for Molecular Medicine, Cambridge, MA; Correspondence and requests for materials should be addressed to Heather Mason-Suares, Laboratory for Molecular Medicine, 65 Landsdowne Street, Cambridge, MA 02139.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.http://www.sciencedirect.com/science/article/pii/S2949774425014694ClinGenNoonanRas/MAPKRASopathyVariant interpretation |
| spellingShingle | 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 Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels Genetics in Medicine Open ClinGen Noonan Ras/MAPK RASopathy Variant interpretation |
| title | Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels |
| title_full | Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels |
| title_fullStr | Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels |
| title_full_unstemmed | Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels |
| title_short | Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels |
| title_sort | updated acmg amp specifications for variant interpretation and gene curations from the clingen rasopathy expert panels |
| topic | ClinGen Noonan Ras/MAPK RASopathy Variant interpretation |
| url | http://www.sciencedirect.com/science/article/pii/S2949774425014694 |
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