Hemochromatosis, a genetic iron overload disorder, is primarily associated with the HFE p.Cys282Tyr variant. However, Shearman et al. (2026) highlight that the p.His63Asp variant has limited clinical significance and its routine inclusion in genetic testing can lead to diagnostic confusion and unnecessary interventions. The authors present five key statements emphasizing that p.His63Asp: (1) has minimal impact on systemic iron metabolism, (2) is not a disease-causing genotype on its own, (3) offers limited utility in evaluating iron overload, (4) should not be used for family or population screenings, and (5) is not recommended for routine reporting in genetic testing. They advocate for focusing on p.Cys282Tyr testing to improve diagnostic accuracy and patient care. Supported by EFAPH and Haemochromatosis International, this review provides clear guidance for patients and healthcare providers.
Shearman J, Olynyk JK, Distante S, Porto G, Sanchez M. HFE and hemochromatosis: time to reconsider the diagnostic role of the p.His63Asp variant. Blood Red Cells & Iron. 2026 Mar;2(1):100034. doi:10.1016/j.brci.2025.100034.