HFE c.187 C>G (H63D)
HFE c.187 C>G is a genetic variant in the HFE gene that is associated with altered regulation of the body's iron metabolism. The mutation leads to a change in the HFE protein where the amino acid histidine is replaced by aspartic acid at position 63, which is called His63Asp or H63D.
The HFE gene is important for the body's control of iron absorption and affects the production of the hormone hepcidin, which regulates how much iron is absorbed from the intestine and stored in the body. In the case of the H63D mutation, this regulation may be affected, which in some individuals may contribute to elevated iron parameters or milder forms of iron overload.
H63D is generally associated with a lower risk of clinically significant hereditary hemochromatosis compared to the H282Y mutation (HFE c.845 G>A). However, the variant is often analyzed together with H282Y in the genetic investigation of suspected hereditary hemochromatosis and iron storage disease.
Why is HFE c.187 C>G analyzed?
Analysis of HFE c.187 C>G is used in the genetic investigation of suspected hereditary hemochromatosis and to identify genetic variants that may affect the body's iron metabolism.
The mutation is often analyzed together with HFE c.845 G>A (H282Y) because the combination of these two mutations may be associated with an increased risk of iron overload.
The result can occur in three different genetic combinations:
- C/C – no detected H63D mutation
- C/G – heterozygous carrier of H63D
- G/G – homozygous carrier of H63D
Individuals who are homozygous carriers (G/G) generally have a low to moderately increased risk of iron metabolism disorders. Most do not develop clinically significant hereditary hemochromatosis, but some individuals may exhibit mildly elevated iron parameters or mild iron overload.
Heterozygous carriers (C/G) do not usually develop iron storage disease but may in some cases show minor changes in iron status.
H63D and hereditary hemochromatosis
The H63D mutation is common in the population and is generally considered a milder genetic variant compared to H282Y. However, the mutation may have greater clinical significance when it occurs in combination with other HFE mutations or together with factors that affect the liver and iron metabolism.
In hereditary hemochromatosis, the body absorbs more iron than it needs, which over time can lead to iron storage in organs and tissues. Pronounced iron storage is seen significantly less frequently in isolated H63D mutations than in homozygous H282Y.
In some individuals, H63D may be associated with:
- slightly elevated ferritin
- increased transferrin saturation
- mild impact on iron metabolism
- increased risk of iron overload in combination with other risk factors.
Application in healthcare
Genetic analysis of HFE c.187 C>G is used in the investigation of suspected hereditary hemochromatosis or in unexplained elevated iron parameters.
The analysis may be relevant in the case of:
- elevated ferritin
- elevated transferrin saturation
- suspected about iron overload
- unexplained liver damage
- investigation of hereditary hemochromatosis
- family investigation in case of known HFE mutation
- symptoms consistent with iron storage disease.
Because hereditary hemochromatosis is an inherited disease, genetic screening of close relatives is sometimes recommended when disease-associated HFE mutations have been identified.
Interpretation of HFE c.187 C>G
HFE 187 G/G (homozygous H63D)
Consistent with homozygous H63D mutation, meaning that the individual carries the mutation on both alleles of the HFE gene. The variant is associated with a mild to moderate increased risk of iron metabolism disorders and milder forms of iron overload. Clinically significant hereditary hemochromatosis is uncommon in isolated H63D homozygosity.
HFE 187 C/G (heterozygous H63D)
Consistent with heterozygous carriership of the H63D mutation. This usually means a low risk of clinically significant iron storage disease but minor effects on iron parameters may occur.
HFE 187 C/C
No H63D mutation detected in the HFE gene.
HFE c.187 C>G and H282Y
In genetic investigation of hereditary hemochromatosis, H63D is often analyzed together with the H282Y mutation (HFE c.845 G>A). Individuals who are double heterozygous, i.e., carriers of both H63D and H282Y, may have an increased risk of milder forms of iron overload and effects on iron parameters.
Double heterozygosity generally implies a lower risk of pronounced iron storage disease compared to homozygous H282Y, but some individuals may develop elevated ferritin or elevated transferrin saturation over time. The genetic risk must always be interpreted together with clinical findings and laboratory analyses such as ferritin, transferrin saturation, iron status and liver tests.
