Abnormally Low Hemoglobin A1c Due to a Heterozygous Alpha-Globin Variant (Hb I; HBA2 c.49A>G, p.Lys17Glu) in a...

Hemoglobin A1c (HbA1c) is central to the screening, diagnosis, and longitudinal management of diabetes mellitus, but numerous physiologic and analytic factors can distort its accuracy. Hemoglobin variants are a well-recognized but frequently underappreciated source of spurious results, and the direction and magnitude of the error are highly method-dependent. We report an asymptomatic 75-year-old woman found to have a profoundly low HbA1c (<3.5%) in the setting of normoglycemia and a normal complete blood count. After exclusion of laboratory error and common confounders, alpha-globin gene sequencing revealed heterozygosity for the HBA2 c.49A>G (p.Lys17Glu) variant, designated Hb I. This variant has normal stability and produces no clinical phenotype in heterozygotes; its significance in this patient lies solely in its interference with HbA1c measurement. This case demonstrates that even a heterozygous, clinically silent alpha-globin variant can render HbA1c uninterpretable, and it emphasizes the particular hazard in older adults, in whom a falsely reassuring HbA1c may mask hyperglycemia or drive inappropriate treatment decisions and hypoglycemia. When HbA1c is unreliable, clinicians should rely on glucose-based diagnostic criteria and on direct glucose measurement (self-monitoring or continuous glucose monitoring), interpreting alternative biomarkers such as fructosamine with caution.