A Rare Hemoglobin Variant (β51Pro → His) Causing Misleading Measurements of Hemoglobin A_1c

Glycated hemoglobin A_1c (HbA_1c) is considered the standard of care for the testing and monitoring of diabetes. Its ability to accurately reflect glycemia, however, is imperfect. Hemoglobin variants-mutant forms of hemoglobin caused by genetic variation present in 7% of the population-are known to adversely affect the ability of HbA_1c measurement to reflect glycemic control. We report an illustrative case of a 64-year-old nondiabetic man with a steadily decreasing HbA_1c and no symptoms of hypoglycemia or concerning family history. Preliminary investigative workup returned nothing of significance. Genetic sequencing, however, identified a rare benign hemoglobin variant: a heterozygous missense mutation in the gene encoding the hemoglobin β chain (c.155C > A, p.Pro51His). This variant has been reported only once previously, and the report predates genetic sequence data of the variant. Although this variant had no clinical implications for the patient, it was the cause of falsely low HbA_1c levels on high-performance ion-exchange chromatography. This case highlights the importance of considering the effect of hemoglobin variants on the measurement of HbA_1c. When available, family history should be carefully considered. Clinicians should suspect hemoglobin variants when HbA_1c is too high or low, or discordant with the clinical picture.