Adapting the ACMG/AMP variant classification framework: a perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel

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.Genetics of disease, diagnosis and treatmen

β+-Thalassemia trait due to a novel mutation in the β-globin gene promoter: -26 (A>C) [HBB c.-76A>C]

We report the case of a woman with β+-thalassemia (β+-thal) trait, in which there were two sequence variants within the β-globin gene promoter: -54 (G>A) [HBB c.-104G>A] and -26 (A>C) [HBB c.-76A>C]. Data from other patients indicate that the -54 substitution is a non pathogenic sequence variant. Therefore, the β-thal phenotype is most likely due to the -26 mutation that is adjacent to the conserved ATAA box. © 2011 Informa Healthcare USA, Inc