ClinGen Hemoglobinopathy VCEP ACMG/AMP specifications for HBB and HBA2 variant interpretation in thalassemia

Background: The ClinGen Hemoglobinopathy Variant Curation Expert Panel (VCEP) was established in 2019 to develop disease-specific adaptations of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) sequence variant interpretation framework for hemoglobinopathies. This study describes the development, validation, and ClinGen approval of the first disease-specific ACMG/AMP specifications for autosomal recessive thalassemia related to HBB and HBA2, providing a standardized framework for globin gene variant interpretation. Methods: Disease-specific ACMG/AMP rule specifications were developed in accordance with ClinGen procedures and Variant Classification Working Group recommendations and evaluated through pilot curation of representative HBB and HBA2 variants using the ClinGen Variant Curation Interface (VCI), with independent biocurator assessment, expert review, and consensus approval. Results: A total of 34 disease-specific evidence specifications were developed across the two gene-disease pairs, encompassing 22 ACMG/AMP evidence criteria and one modification to the ACMG/AMP evidence-combining rules. Pilot application to 33 representative variants (20 HBB, 13 HBA2) demonstrated high concordance with established pathogenic and benign classifications while providing a standardized framework for resolving variants with conflicting or limited evidence. Following pilot validation, the specifications received ClinGen approval, and all curated variants with supporting evidence were disseminated through the ClinGen Evidence Repository (ERepo) and ClinVar. Conclusions: The ClinGen Hemoglobinopathy VCEP specifications provide the first ClinGen-approved disease-specific ACMG/AMP rule specifications for HBB and HBA2 variants related to thalassemia. These specifications establish a robust and transparent framework for harmonized globin variant interpretation and provide a foundation for sustained expert curation, continued refinement through emerging evidence, and expansion to additional hemoglobinopathy gene-disease pairs.