Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource’s FBN1 variant curation expert panel
Abstract Background In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed standardized variant curation guidelines for Mendelian disorders. Although these guidelines have been widely adopted, they are not gene- or disease-sp...
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| author | A. Drackley C. Somerville P. Arnaud L. M. Baudhuin N. Hanna M. L. Kluge K. Kotzer C. Boileau L. Bronicki B. Callewaert A. Cecchi H. Dietz D. Guo S. Harris O. Jarinova M. Lindsay L. Little B. Loeys G. MacCarrick J. Meester D. Milewicz T. Morisaki H. Morisaki D. Murdock M. Renard J. Richer L. Robert M. Ouzounian L. Van Laer J. De Backer L. Muiño-Mosquera |
| author_facet | A. Drackley C. Somerville P. Arnaud L. M. Baudhuin N. Hanna M. L. Kluge K. Kotzer C. Boileau L. Bronicki B. Callewaert A. Cecchi H. Dietz D. Guo S. Harris O. Jarinova M. Lindsay L. Little B. Loeys G. MacCarrick J. Meester D. Milewicz T. Morisaki H. Morisaki D. Murdock M. Renard J. Richer L. Robert M. Ouzounian L. Van Laer J. De Backer L. Muiño-Mosquera |
| author_sort | A. Drackley |
| collection | DOAJ |
| description | Abstract Background In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed standardized variant curation guidelines for Mendelian disorders. Although these guidelines have been widely adopted, they are not gene- or disease-specific. To mitigate classification discrepancies, the Clinical Genome Resource FBN1 variant curation expert panel (VCEP) was established in 2018 to develop adaptations to the ACMG/AMP criteria for FBN1 in association with Marfan syndrome. Methods The specific recommendations were developed through literature review, surveys, online expert panel discussions, and pilot testing of a set of 60 different variants. Consensus among experts was considered reached if at least 75% of the members agreed with a given rule specification. The final set of rules received approval from the ClinGen Sequence Variant Interpretation Working Group. Results The developed specifications introduce modifications to 14 of the 28 ACMG/AMP evidence criteria and deem 6 criteria non-applicable. Some of these specifications include refining the minor allele frequency thresholds, creating a FBN1-specific flowchart for PVS1, defining functional domains of the protein, developing a point-based system of counting probands and instances of de novo occurrences, recommending a points-based method of accounting for family segregation data, and clarifying the applicable functional assays that should be considered. To date, this VCEP has curated 120 variants which have been deposited to ClinVar with the 3-star review status. Conclusions Establishing specific adaptations for FBN1 has provided a framework to foster greater classification concordance among clinical laboratories, ultimately improving clinical care for patients with Marfan syndrome. |
| format | Article |
| id | doaj-art-87697616f38742e28a4f6455d825e8e2 |
| institution | Kabale University |
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| language | English |
| publishDate | 2024-12-01 |
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| spelling | doaj-art-87697616f38742e28a4f6455d825e8e22025-01-05T12:42:19ZengBMCGenome Medicine1756-994X2024-12-0116111410.1186/s13073-024-01423-3Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource’s FBN1 variant curation expert panelA. Drackley0C. Somerville1P. Arnaud2L. M. Baudhuin3N. Hanna4M. L. Kluge5K. Kotzer6C. Boileau7L. Bronicki8B. Callewaert9A. Cecchi10H. Dietz11D. Guo12S. Harris13O. Jarinova14M. Lindsay15L. Little16B. Loeys17G. MacCarrick18J. Meester19D. Milewicz20T. Morisaki21H. Morisaki22D. Murdock23M. Renard24J. Richer25L. Robert26M. Ouzounian27L. Van Laer28J. De Backer29L. Muiño-Mosquera30Department of Pathology & Laboratory Medicine, Ann & Robert H. Lurie Children’s Hospital of ChicagoGenetics Diagnostic Laboratory, Children’s Hospital of Eastern OntarioGenetics Department, Hôpital Bichat, Université Paris CitéDepartment of Laboratory Medicine and Pathology, Mayo ClinicGenetics Department, Hôpital Bichat, Université Paris CitéDepartment of Laboratory Medicine and Pathology, Mayo ClinicDepartment of Laboratory Medicine and Pathology, Mayo ClinicGenetics Department, Hôpital Bichat, Université Paris CitéGenetics Diagnostic Laboratory, Children’s Hospital of Eastern OntarioCentre for Medical Genetics, Ghent University HospitalDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at HoustonMcKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of MedicineDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at HoustonCardiovascular Research Center, Massachusetts General HospitalGenetics Diagnostic Laboratory, Children’s Hospital of Eastern OntarioCardiovascular Research Center, Massachusetts General HospitalGenetics Diagnostic Laboratory, Children’s Hospital of Eastern OntarioEuropean Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD and MSA Rare Disease, Working GroupMcKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of MedicineEuropean Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD and MSA Rare Disease, Working GroupDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at HoustonIMSUT Hospital, The Institute of Medical Science, The University of TokyoIMSUT Hospital, The Institute of Medical Science, The University of TokyoDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at HoustonCentre for Medical Genetics, Ghent University HospitalDepartment of Medical Genetics, Children’s Hospital of Eastern OntarioDepartment of Cardiology, Guy’s and St Thomas’ Foundation TrustDivision of Cardiac Surgery, University of TorontoEuropean Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD and MSA Rare Disease, Working GroupEuropean Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD and MSA Rare Disease, Working GroupEuropean Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD and MSA Rare Disease, Working GroupAbstract Background In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed standardized variant curation guidelines for Mendelian disorders. Although these guidelines have been widely adopted, they are not gene- or disease-specific. To mitigate classification discrepancies, the Clinical Genome Resource FBN1 variant curation expert panel (VCEP) was established in 2018 to develop adaptations to the ACMG/AMP criteria for FBN1 in association with Marfan syndrome. Methods The specific recommendations were developed through literature review, surveys, online expert panel discussions, and pilot testing of a set of 60 different variants. Consensus among experts was considered reached if at least 75% of the members agreed with a given rule specification. The final set of rules received approval from the ClinGen Sequence Variant Interpretation Working Group. Results The developed specifications introduce modifications to 14 of the 28 ACMG/AMP evidence criteria and deem 6 criteria non-applicable. Some of these specifications include refining the minor allele frequency thresholds, creating a FBN1-specific flowchart for PVS1, defining functional domains of the protein, developing a point-based system of counting probands and instances of de novo occurrences, recommending a points-based method of accounting for family segregation data, and clarifying the applicable functional assays that should be considered. To date, this VCEP has curated 120 variants which have been deposited to ClinVar with the 3-star review status. Conclusions Establishing specific adaptations for FBN1 has provided a framework to foster greater classification concordance among clinical laboratories, ultimately improving clinical care for patients with Marfan syndrome.https://doi.org/10.1186/s13073-024-01423-3Marfan syndromeFBN1ACMG-AMP guidelinesVariant interpretationVariant curation |
| spellingShingle | A. Drackley C. Somerville P. Arnaud L. M. Baudhuin N. Hanna M. L. Kluge K. Kotzer C. Boileau L. Bronicki B. Callewaert A. Cecchi H. Dietz D. Guo S. Harris O. Jarinova M. Lindsay L. Little B. Loeys G. MacCarrick J. Meester D. Milewicz T. Morisaki H. Morisaki D. Murdock M. Renard J. Richer L. Robert M. Ouzounian L. Van Laer J. De Backer L. Muiño-Mosquera Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource’s FBN1 variant curation expert panel Genome Medicine Marfan syndrome FBN1 ACMG-AMP guidelines Variant interpretation Variant curation |
| title | Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource’s FBN1 variant curation expert panel |
| title_full | Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource’s FBN1 variant curation expert panel |
| title_fullStr | Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource’s FBN1 variant curation expert panel |
| title_full_unstemmed | Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource’s FBN1 variant curation expert panel |
| title_short | Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource’s FBN1 variant curation expert panel |
| title_sort | interpretation and classification of fbn1 variants associated with marfan syndrome consensus recommendations from the clinical genome resource s fbn1 variant curation expert panel |
| topic | Marfan syndrome FBN1 ACMG-AMP guidelines Variant interpretation Variant curation |
| url | https://doi.org/10.1186/s13073-024-01423-3 |
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