ACMG/AMP-Based Variant Classification of a Novel HBA2 Variant (HBA2: C.297del, Hb Taiping) in Compound Heterozygosity With Hb Adana (HBA2:C.179G>A) Causing Non-Deletional Hb H Disease.

backgroundAccurate classification of novel globin gene variants is critical for the diagnosis and management of thalassaemia. The adaptation of ACMG/AMP guidelines for globin genes represents an important step toward standardising variant interpretation and enhancing clinical utility in the field. This study reports the haematological and molecular characteristics of a novel α2-globin variant identified in a Malay family.

methodsA Malay family from Taiping, Perak, Malaysia, with a history of α-thalassaemia, was recruited for this study. The proband's phenotype was assessed through comprehensive haematological analysis and clinical evaluation. Known α-thalassaemia deletions and non-deletional mutations were screened using gap-PCR and ARMS-PCR. Sanger sequencing of the HBA genes was conducted to characterise the proband's genotype in detail.

resultsA novel pathogenic HBA2 variant was identified, expanding the known mutational spectrum of α-thalassaemia. This variant introduces a premature stop codon, occurs in trans with a known pathogenic allele associated with a significant clinical phenotype, segregates with the disease in the family, and is absent from major population databases. Based on haematological data, molecular findings, in silico predictions, and protein modeling, the variant meets the ACMG/AMP criteria for pathogenicity adapted for α-globin genes. We have designated this variant Hb Taiping, named after the location of its discovery. Its accurate classification is vital for carrier screening, genetic counselling, and prenatal diagnosis, thereby supporting improved clinical management.

conclusionThis study identifies and characterises a novel α-globin gene variant, Hb Taiping, in a Malay family with α-thalassaemia. The discovery contributes to the growing body of pathogenic mutations linked to α-thalassaemia and underscores the importance of precise variant classification for effective diagnosis, risk assessment, and genetic counselling.