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

ClinGen Hemoglobinopathy VCEP developed and ClinGen-approved the first disease-specific ACMG/AMP specifications for autosomal recessive thalassemia variants in HBB and HBA2, totaling 34 evidence specifications.

• Why it matters: Existing ACMG/AMP rules needed hemoglobinopathy-specific adaptations to standardize how globin gene variants are interpreted, especially when evidence is conflicting or limited.
• What they did: The team created 34 disease-specific evidence specifications (22 ACMG/AMP criteria plus one evidence-combining rule modification) and piloted them on 33 representative variants using the ClinGen Variant Curation Interface with independent biocurator assessment and consensus.
• The result: Pilot curation showed high concordance with established pathogenic and benign classifications, and the approved specifications were released via the ClinGen Evidence Repository and ClinVar.

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