H63D

H63D is a missense variant in the HFE gene, resulting in a histidine-to-aspartic acid substitution at amino acid position 63 (p.H63D). It is one of several variants associated with hereditary hemochromatosis, a disorder of iron overload. The HFE protein is involved in regulating iron absorption by influencing the activity of the transferrin receptor and the production of the iron-regulatory hormone hepcidin. The H63D change can alter HFE function and iron homeostasis, but its clinical impact is variable.

The H63D variant is relatively common in populations of European descent. In most individuals, H63D alone does not cause clinically significant iron overload. Disease risk is higher when H63D is present in combination with another pathogenic HFE allele, particularly C282Y (as compound heterozygosity), or rarely when present in homozygous form. Even then, penetrance is variable, and many individuals with H63D-related genotypes have mild or no iron overload.

Clinical presentation, when it occurs, ranges from asymptomatic laboratory findings to signs of iron overload such as fatigue, abdominal discomfort, liver disease, diabetes, arthritis, or skin hyperpigmentation. Diagnosis relies on genetic testing for H63D and related variants (notably C282Y) alongside iron studies including ferritin and transferrin saturation. Management focuses on treating iron overload if present, typically through phlebotomy to reduce ferritin levels, along with monitoring and addressing liver health and metabolic risk factors. Family history and genetic counseling are often recommended due to autosomal recessive inheritance and the potential for affected relatives.