HFE

Gene Facts

• HGNC Symbol: HFE (HGNC:4886)
• HGNC Name: homeostatic iron regulator
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: HLA-H, HFE1
• %HI: 74.41
• pLI: 0
• LOEUF: 1.04
• Cytoband: 6p22.2
• Genomic Coordinates:

  GRCh37/hg19:	chr6:26087657-26098571
  GRCh38/hg38:	chr6:26087429-26098343

• MANE Select Transcript: NM_000410.4 ENST00000357618.10
• Function: Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin. {ECO:0000269|PubMed:9465039}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-36616
• ClinGen Curation ID: CCID:007277
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Gene Associated with Autosomal Recessive Phenotype (30)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Yes
  Schmidtke et al. (PMID: 36140790) reviewed previous studies aiming to address the issues of population screening of Hereditary Hemochromatosis (HH). It was found that the biochemical penetrance (elevated levels of serum ferritin and transferrin saturation) is 40 -60% for female p.Cys282Tyr/p.Cys282Tyr homozygotes and 75-100% for male homozygotes. If use serum ferritin levels of 1000 ug/L as the cut-off, the penetrance of individuals with homozygous p.Cys282Tyr/p.Cys282Tyr is 35% for males and 6% for females at a median age of 65 years. The clinical penetrance varies from different studies. If use full-blown clinical phenotype as the evaluation criteria (i.e. a combination of liver disease, heart failure, diabetes mellitus and bronze skin), the penetrance of homozygous p.Cys282Tyr/p.Cys282Tyr for clinical HH is less than 1%. A cross-sectional study using liver disease as a proxy demonstrated a penetrance of 1.4% for newly diagnosed homozygous p.Cys282Tyr/p.Cys282Tyr individuals. If using life-time incidence as a way of evaluation, it is estimated that roughly 1 in 10 male homozygous p.Cys282Tyr/p.Cys282Tyr individuals will develop liver disease if untreated and the overall clinical penetrance in terms of iron overload related symptoms is around 28% in males. For p.Cys282Tyr/p.His63Asp compound heterozygotes, it is estimated that 0.5 – 2% of such individuals develop clinical evidence of iron overload. The penetrance for homozygous p.His63Asp/p.His63Asp is lower than p.Cys282Tyr/p.His63Asp compound heterozygotes, while biochemical iron overload may presence, clinical presentation is rare. (references cited in the review: PMID: 10471457; PMID: 28771247; PMID:15858186; PMID: 11812557; PMID: 15070663; PMID: 16039334; PMID: 19554541; PMID: 11874997)
• Last Evaluated: 04/08/2024

Haploinsufficiency (HI) Score Details

• HI Score: 30
• HI Evidence Strength: Gene Associated with Autosomal Recessive Phenotype

HI Disease

• hereditary hemochromatosis

HI Evidence

• PUBMED: 22093335
  A 43-year-old Japanese male patient diagnosed with Hereditary Haemochromatosis with elevated serum iron level (280 ug/dl), hyperferritinemia (1,698 ng/ml) and low serum level of hepcidine-25 (4.0 ng/ml). Abdominal MRI revealed iron accumulation in the liver and pancreas. HFE gene sequencing detected a novel homozygous c.691_693del, p.Tyr231del variant. Huh-7, a hepatoma cell line harboring this variant, was shown that the HFE protein failed to reach plasma membrane and did not colocalize with membrane-expressed beta(2)M. Similar effect as exogenously expressed p.Cys282Tyr mutant.
• PUBMED: 20117027
  Among 12 patients with iron overload (increased transferrin saturation, serum ferritin and hepatic iron stores) and heterozygous for p.Cys282Tyr variant, second allele were identified in four patients, one is missense variant (p.Arg66Cys) and the other three is truncating variants (p.Gln233X, p.Try169X and p.Glu168X).
• PUBMED: 17951290
  A panel sequencing of genes involving iron metabolism (HFE, HAMP, HFE2/HJV, SLC40A1, TFR2, 5’UTR of FTL) was carried out for 38 patients had a diagnosis of Hereditary Hemochromatosis (16 patients) or Hereditary Hyperferritinemia (22 patients). One patient was detected to harbor compound heterozygous variants: p.Cys282Tyr and c.794dupA, p.Trp267LeufsX80. His daughter carries the c.794dupA variant and is asymptomatic.
• PUBMED: 24920245
  HFE gene sequencing was carried out for 22 patients with severe biochemical iron overload (BIO) and heterozygous for p.His63Asp variant, a homozygous c.847C>T,p.Gln283* pathogenic variant was detected. HFE mRNA level in patient is significantly lower than that of the controls.
• PUBMED: 18809761
  A homozygous HFE gene deletion was detected in a 47-year old woman with moderate iron overload. The deletion was determined to be caused by Alu-mediated recombination. The deletion results from a founder effect in Sardinia population. The carrier frequency of the deletion is estimated to be 2.02% in this population (0.5% for the p.Cys282Tyr variant).

• HI Evidence Comments: HFE gene mutations are associated with adult-onset autosomal recessive hemochromatosis. Various homozygous or compound heterozygous mutations, including missense (most common), nonsense, splice-site, small deletions and complete gene deletion (only detected in Sardinia) have been described in the literature. Although various mutations of HFE cause hemochromatosis, most of the affected individuals of European descent have either homozygous p.Cys282Tyr (p.282C>Y) mutation or compound heterozygous p.Cys282Tyr (p.282C>Y) and p.His63Asp (p.63H>D) mutations. HEF variants and association with cancer predisposition Liu et al. 2013 PMID: 23681799 A meta-analysis to investigate the association of common HFE variants and cancer predisposition. This analysis is based on 7 studies including 1,720 cases and 18,296 controls for HFE p.Cys282Tyr and 5 studies including 942 cases and 1,571 controls for HFE p.His63Asp. It was shown that the homozygous HFE p.Cys282Tyr was significantly associated with an increased risk of breast cancer under homozygotes vs. wild type model (OR=2.06, 95%CI=1.19-3.58) and recessive model (homozygous for p.Cys282Tyr genotype vs. Heterozygous for p.Cys282Tyr + Wild type; OR=1.98, 95%CI=1.14-3.44) but not under heterozygous vs. wild-type model (OR=0.97, 95%CI=0.70-1.35), dominant model (OR=1.00, 95%CI=0.72-1.40) and multiplicative model (OR=1.04, 95%CI=0.76-1.42). No associations were found for HFE p.His63Asp variant. Zhang et al. 2015 PMID: 26107216 This meta-analysis aims to address the HFE p.Cys282Tyr and p.His63Asp variants and their associations with cancers. This study includes 20 publications including 24 case control studies comprising 6,524 cases and 31,080 controls for HFE p.Cys282Tyr variant and 19 publications including 21 case control studies, comprising 5,648 cases and 14,257 controls for p.His63Asp variant. The odds ratio is 1.428 (95% CI=1.017-2.006, pheterogeneity=0.220) for overall cancer risk for p.Cys282Tyr homozygotes vs. wild type. The odds ratio for p.His63Asp variant is between 1.1153 – 1.449 for different association models ( (allele contrast, dominant model, recessive model). In a stratified analyses by cancer types, p.Cys282Tyr has an increased risk for hepatocellular carcinoma and breast cancer and p.His63Asp is associated with an increased for pancreatic cancer. Natarajan et al. 2023 PMID: 35790703 A retrospective cohort study of 5,225 patients in the Veterans Health Administration system on the association of different genotypes of HFE gene and hepatocellular carcinoma (HCC). The incidence rates (IRs) of HCC for p.Cys282Tyr/Cys282Tyr is 5.59/1000 PYs, p.Cys282Tyr/p.His63Asp is 4.12/1000PYs. The IRs for these two genotypes are significantly higher than controls (0.92/1000 PYs) with adjusted hazard ratio of 8.80 (95% CI 4.17-18.54) and 5.28 (95% CI 2.24 -12.32) respectively. The adjusted hazard ratio for H63D heterozygous is 2.82 (95%CI 1.21-6.58). Pathogenic variants in HFE gene exhibit an autosomal recessive manner for Hereditary Hemochromatosis. It is inconclusive whether the heterozygous status of the common variants in the HFE gene are associated with an increased risk of cancers.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity