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Adapting the ACMG/AMP variant classification framework: A perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel
Author(s) -
Kountouris Petros,
Stephanou Coralea,
Lederer Carsten W.,
TraegerSynodinos Joanne,
Bento Celeste,
Harteveld Cornelis L.,
Fylaktou Eirini,
Koopmann Tamara T.,
HalimFikri Hashim,
Michailidou Kyriaki,
Nfonsam Landry E.,
Waye John S.,
Zilfalil Bin A.,
Kleanthous Marina
Publication year - 2022
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24280
Subject(s) - medical genetics , genomics , biology , computational biology , genetics , bioinformatics , computer science , genome , gene
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.