Hemochromatosis (HFE) 3 Variants

Last Literature Review: April 2022 Last Update:

Use to confirm clinical diagnosis of HH in an individual with biochemical findings of iron overload, to screen adult family members of individuals with known HH, or to test the reproductive partner of an individual with HH for carrier status. Not recommended for initial hemochromatosis testing.

Hereditary hemochromatosis (HH) is a common genetic disorder that is most prevalent in adult males of northern European descent. The most common form of adult HH has been linked to variants (C282Y, H63D, and S65C) of the HFE gene, which codes for a protein responsible for iron regulation. Allele frequency varies by ethnicity. The severity of the causative variant correlates with the time course of iron overload and organ damage; more severe variants lead to pediatric onset of symptoms, while less severe variants may lead to adult symptom onset or may never result in symptoms. If left untreated, HH may lead to liver disease, skin hyperpigmentation, diabetes mellitus, or heart disease.




  • p.C282Y (c.845G>A)
  • p.H63D (c.187C>G)
  • p.S65C (c.193A>T)


Pathogenic variants in the HFE gene result in increased iron absorption even in cases of normal dietary iron intake. HFE variants may lead to a high rate of iron absorption across duodenal enterocytes and/or excessive parenchymal storage of iron with end-organ damage.


Autosomal recessive

Test Interpretation

Clinical Sensitivity

Up to 90% for White populations,  lower in other ethnicities

Analytic Sensitivity/Specificity



Interpretations for Common HFE Gene Variants
Variant Patient Presentation for Clinical and Biochemical Evidence of Iron Overload Comments

C282Y, H63D, S65C heterozygosity; H63D homozygosity

May have elevated serum iron levels

Positive clinical symptoms only if an additional rare, undetected HFE variant is present

Negative clinical symptoms of iron overload

Consider HFE or other alternative full gene sequencing and possibly deletion/duplication analysis if suspicion for HH remains high

C282Y homozygosity


High risk for iron overload

Only a minority develop clinical symptoms


Confirms diagnosis of HH

Only a minority develop clinical symptoms

C282Y/H63D; C282Y/S65C

compound heterozygosity


Moderate risk of iron overload

<2% risk of developing clinical symptoms


Supports a diagnosis of HH

Penetrance is low: only a minority develop clinical symptoms


  • Lack of detection of one of three HFE variants does not eliminate the possibility of HH
    • Rare HFE variants and those in other iron-related genes are not detected by this test
  • Rare diagnostic errors may occur due to primer-site variations
  • Genotyping does not substitute for serum iron studies, which identify iron overload


Additional Resources