Adapting the ACMG/AMP variant classification framework: A perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel
Human Mutation, vol. 43, pp. 1089–1096
Abstract
Accurate and consistent interpretation of sequence variants is integral to the delivery of safe and reliable diagnostic genetic services. To standardize the interpretation process, in 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published a joint guideline based on a set of shared standards for the classification of variants in Mendelian diseases. The generality of these standards and their subjective interpretation between laboratories has prompted efforts to reduce discordance of variant classifications, with a focus on the expert specification of the ACMG/AMP guidelines for individual genes or diseases. Herein, we describe our experience as a ClinGen Variant Curation Expert Panel to adapt the ACMG/AMP criteria for the classification of variants in three globin genes (HBB, HBA2, and HBA1) related to recessively inherited hemoglobinopathies, including five evidence categories, as use cases demonstrating the process of specification and the underlying rationale.
Authors 14
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Petros Kountouris corresponding
Cyprus Institute of Neurology and Genetics
Affiliation as printed
Cyprus School of Molecular Medicine Nicosia Cyprus
Molecular Genetics Thalassaemia Department The Cyprus Institute of Neurology and Genetics Nicosia Cyprus
Cyprus School of Molecular Medicine, Nicosia, Cyprus
Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Cyprus Institute of Neurology and Genetics
Affiliation as printed
Molecular Genetics Thalassaemia Department The Cyprus Institute of Neurology and Genetics Nicosia Cyprus
Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Cyprus Institute of Neurology and Genetics
Affiliation as printed
Cyprus School of Molecular Medicine Nicosia Cyprus
Molecular Genetics Thalassaemia Department The Cyprus Institute of Neurology and Genetics Nicosia Cyprus
Cyprus School of Molecular Medicine, Nicosia, Cyprus
Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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National and Kapodistrian University of Athens
Affiliation as printed
Laboratory of Medical Genetics, St. Sophia's Children's Hospital National and Kapodistrian University of Athens Athens Greece
Laboratory of Medical Genetics, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Unidade Local de Saúde de Coimbra
Affiliation as printed
Department of Haematology Centro Hospitalar e Universitário de Coimbra Coimbra Portugal
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Cornelis L. Harteveld Aachen Department of Clinical Genetics/LDGA Leiden University Medical Center Leiden Netherlands Department of Clinical Genetics/LDGA
Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics/LDGA Leiden University Medical Center Leiden Netherlands
Department of Clinical Genetics/LDGA, Leiden University Medical Center, Leiden, Netherlands
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National and Kapodistrian University of Athens
Affiliation as printed
Laboratory of Medical Genetics, St. Sophia's Children's Hospital National and Kapodistrian University of Athens Athens Greece
Laboratory of Medical Genetics, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Tamara T. Koopmann Aachen Department of Clinical Genetics/LDGA Leiden University Medical Center Leiden Netherlands Department of Clinical Genetics/LDGA
Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics/LDGA Leiden University Medical Center Leiden Netherlands
Department of Clinical Genetics/LDGA, Leiden University Medical Center, Leiden, Netherlands
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Affiliation as printed
School of Medical Sciences Universiti Sains Malaysia Malaysia
School of Medical Sciences, Universiti Sains Malaysia, Malaysia
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Cyprus Institute of Neurology and Genetics
Affiliation as printed
Biostatistics Unit The Cyprus Institute of Neurology and Genetics Nicosia Cyprus
Cyprus School of Molecular Medicine Nicosia Cyprus
Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
Cyprus School of Molecular Medicine, Nicosia, Cyprus
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Hamilton Regional Laboratory Medicine Program · Hamilton Health Sciences · McMaster University
Affiliation as printed
Department of Pathology and Molecular Medicine McMaster University Hamilton Canada
Hamilton Regional Laboratory Medicine Program Hamilton Health Sciences Hamilton Canada
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Canada
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Hamilton Regional Laboratory Medicine Program · Hamilton Health Sciences · McMaster University
Affiliation as printed
Department of Pathology and Molecular Medicine McMaster University Hamilton Canada
Hamilton Regional Laboratory Medicine Program Hamilton Health Sciences Hamilton Canada
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Canada
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Affiliation as printed
School of Medical Sciences Universiti Sains Malaysia Malaysia
School of Medical Sciences, Universiti Sains Malaysia, Malaysia
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Cyprus Institute of Neurology and Genetics
Affiliation as printed
Cyprus School of Molecular Medicine Nicosia Cyprus
Molecular Genetics Thalassaemia Department The Cyprus Institute of Neurology and Genetics Nicosia Cyprus
Cyprus School of Molecular Medicine, Nicosia, Cyprus
Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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