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This case describes how an inconsistent Hb A1c result disclosed the presence of a rare hemoglobin variant after a change of method. The variant was not seen and did not affect Hb A1c with the previous method (HPLC), but it was seen and did affect Hb A1c with the new method (capillary electrophoresis). This seems a paradox as capillary electrophoresis has a higher resolution than HPLC. Hemoglobin variants can affect the reliability of Hb A1c for (a) analytical and (b) physiological reasons. Measured Hb A1c is derived from the ratio of measured glycated and non-glycated (total) hemoglobin. If, in the case of a variant, part of the glycated hemoglobin is not measured, Hb A1c will be too low, leading to undertreatment. If part of the non-glycated hemoglobin is not measured, then the opposite applies. The common variants S, C, E, and D do not interfere with most methods, but results can be different for rare variants, as has been reported for 49 variants (1), and is unknown for many of the more than 300 β-chain variants described in the literature (2). Hb A1c depends on the glucose levels over the last 3 months but also on the lifespan of red cells. In certain physiological conditions, such as (variant-related) anemia and kidney diseases, the red cell lifespan can be significantly altered leading to under- or overtreatment.

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