HFE H63D - GET-Evidence

Curation:

(See latest approved version)
Currentness:

HFE H63D

(HFE His63Asp)


Short summary

There have been some hypotheses that this variant contributes to causing hereditary hemochromatosis, possibly as a compound heterozygote, but some others treat it as a polymorphism. Cys282Tyr is the classic causal variant and itself has very low penetrance. Mouse studies indicates this variant has a similar but weaker effect; if it has any effect at all its penetrance may be quite low and/or require modifier alleles.

Variant evidence
Computational 2

Gene is associated with the disease, disruptive amino acid change

See unpublished research (below).

Functional 2

This variant appears to inhibit iron export, and mice carrying it have increased hepatic iron loading but less severe than the Cys282Tyr mutation.

See 12429850, Tomatsu S et al. 2003 (14673107).

Case/Control

Case/control data is mixed.

See Feder JN et al. 1996 (8696333), A simple genetic test identifies 90% of UK patients with haemochromatosis 1997 (9462220).

Familial
 
Clinical importance
Severity 4

Hereditary hemachromatosis can cause organ damage if untreated.

Treatability 5

Phlebotomy treatment maintains normal iron balance

Penetrance 1

Very low penetrance if pathogenic

 

Impact

Low clinical importance, Uncertain pathogenic

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

From ExPASy Proteomics Server:
Hereditary hemochromatosis (HH)
Defects in HFE are a cause of hereditary hemochromatosis (HH) OMIM#235200. HH is an autosomal recessive inborn disorder of iron metabolism. It is the most common recessive disease in Caucasians. HH is characterized by abnormal intestinal iron absorption and progressive increase of total body iron, which results in midlife in clinical complications including cirrhosis, cardiopathy, diabetes, endocrine dysfunctions, arthropathy, and susceptibility to liver cancer. Since the disease complications can be effectively prevented by regular phlebotomies, early diagnosis is most important to provide a normal life expectancy to the affected subjects

Total cases/controls case+ case– control+ control– p-value odds ratio
HFE-Associated Hereditary Hemochromatosis
22 259 79 431 0.0018 0.463

 

Allele frequency

  • G @ chr6:26091179: 11.0% (1183/10758) in EVS
  • G @ chr6:26199157: 6.2% (8/128) in GET-Evidence
  • Frequency shown in summary reports: 11.0% (1183/10758)

Publications
 

Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996 Aug;13(4):399-408. PubMed PMID: 8696333.

In nine patients already found to be heterozygous for Cys282Tyr, they found that 8 out of the 9 “non-ancestral chromosomes” (?) contained this variant, compared to 51 out of 308 control chromosomes (p < 10^-4). In 21 remaining patients without Cys282Tyr, out of 42 chromosomes 9 carried the His62 variant, no higher than control frequency. (The combined numbers are case+: 17, case-: 34, control+: 51, control-: 257, which has p = .007 and OR = 2.5) The authors hypothesize that this variant is only causal for the disease in the presence of the Cys282.

Cases/controls case+ case– control+ control– p-value odds ratio
HFE-Associated Hereditary Hemochromatosis
17 34 51 257 0.0070 2.520

 

A simple genetic test identifies 90% of UK patients with haemochromatosis. The UK Haemochromatosis Consortium. Gut. 1997 Dec;41(6):841-4. PubMed PMID: 9462220; PubMed Central PMCID: PMC1891611.

115 unrelated patients with hereditary haemochromatosis and 101 controls were genotyped. The H63D variant was present in 5 of the 230 patient chromosomes and 28 of the 202 control chromosomes, contradicting a link with the disease. In contrast, there was a very high rate of C282Y mutations in patients (105 out of 115 were homozygous for this compared to 1 out of 101 controls).

Cases/controls case+ case– control+ control– p-value odds ratio
HFE-Associated Hereditary Hemochromatosis
5 225 28 174 0.0000 0.138

 

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PubMed PMID: 12429850

H41 here refers to the position in the mature protein, which corresponds to H63 in the immature protein.

Tomatsu S, Orii KO, Fleming RE, Holden CC, Waheed A, Britton RS, Gutierrez MA, Velez-Castrillon S, Bacon BR, Sly WS. Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15788-93. Epub 2003 Dec 12. PubMed PMID: 14673107; PubMed Central PMCID: PMC307646.

 

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PubMed PMID: 17042772

Abstract: “OBJECTIVES: Hereditary haemochromatosis is a disease that affects iron metabolism and leads to iron overload. Homozygosity for the H63D mutation is associated with increased transferrin saturation (TS) and ferritin levels. Our objective was to find out if the homozygosity of H63D mutation was the primary cause of iron overload. PATIENTS AND METHODS: We studied 45 H63D homozygotes (31 males and 14 females) with biochemical iron overload and/or clinical features of haemochromatosis. The simultaneous detection of 18 known HFE, TFR2 and FPN1 mutations and sequencing of the HAMP gene were performed to rule out the possible existence of genetic modifier factors related with iron overload. RESULTS: Values of biochemical iron overload, measured as percentage TS and serum ferritin concentration (SF), in our H63D homozygotes were significantly higher in patients than in controls: TS 55 +/- 15% vs. 35 +/- 15% and SF 764 (645-883) microg/L vs. 115 (108-123) microg/L for patients and controls, respectively. These H63D homozygotes presented extreme hyperferritinaemia and no additional mutations in HFE, TFR2, FPN1 and HAMP genes were detected. CONCLUSIONS: The lack of additional mutations in our H63D homozygotes suggests that this genotype could be the primary cause of iron overload in these patients. Despite our results, we cannot entirely discount the possibility that one or more genetic modifier factor exists, simply because we were unable to find it, although there was a precedent in the HFE gene. Genetic modifier factors have been described for C282Y mutations in the HFE gene, but at the present time they have never been reported in H63D homozygotes.”

Genomes
 

 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het G @ chr6:26091179

 

 

 

 

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het G @ chr6:26091179

 

 

GS06985 - var-GS06985-1100-36-ASM
het G @ chr6:26199158

 

GS18526 - var-GS18526-1100-36-ASM
het G @ chr6:26199158

 

GS19735 - var-GS19735-1100-36-ASM
het G @ chr6:26199158

 

Other external references
 

    dbSNP
  • rs1799945
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.999 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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