P135: THE CLINGEN HEMOGLOBINOPATHY VARIANT CURATION EXPERT PANEL

Abstract

Background: 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 different lines of evidence for the classification of sequence variants in Mendelian diseases. The generality of this guideline necessitates the application of expert judgment when evaluating and weighing evidence for variant interpretation. The Clinical Genome Resource (ClinGen) assembles Variant Curation Expert Panels (VCEPs) to perform gene- and disease-specific modifications of the ACMG/AMP framework. The ClinGen Hemoglobinopathy VCEP was created collaboratively between the ITHANET portal and the Global Globin Network of the Human Variome Project towards comprehensive annotation of all variants related to hemoglobinopathies. Aim: The adaptation of the ACMG/AMP variant interpretation guidelines of use in hemoglobinopathies. Methods: The Hemoglobinopathy VCEP focuses on the review and annotation of variants located in the globin gene clusters, namely α-globin locus (NG_000006), which includes genes HBA1, HBA2 and HBZ, and β-globin locus (NG_000007) which includes genes HBB, HBD, HBG1, HBG2 and HBE and the regulatory element LCRB. Using a consensus approach and guidance by the ClinGen Sequence Variant Interpretation Working Group, the Hemoglobinopathy VCEP has prepared a pre-final version of the specified ACMG/AMP criteria for hemoglobinopathies. Results: The Hemoglobinopathy VCEP developed disease-specific rules for sequence variant classification based on evidence criteria that assess variant frequency, variant types and disease causality, protein domains and mutational hotspots implicated in disease, clinical manifestations, segregation, in silico predictions and functional evidence. Conclusions: For the first time, the Hemoglobinopathy VCEP will provide a standardised classification of the pathogenicity of variants related to hemoglobinopathies. The Hemoglobinopathy VCEP specifications were approved by ClinGen in April 2021 (Step 2 approval), which initiated the process of further validation and adaptation with known globin gene variants in a pilot study (toward Step 3 approval). References 1. Kountouris P et al, Human Mutation 2021, doi: 10.1002/humu.24280