HFE C282Y - GET-Evidence

Curation:
Currentness:

HFE C282Y

(HFE Cys282Tyr)


Short summary

This variant is associated with hereditary haemochromatosis, 80% of patients with that disease are homozygous for this variant. However, the penetrance is low, in Beutler et al. they note that only 1 of their 158 homozygotes met criteria for diagnosis with the condition.

Variant evidence
Computational 2

Another variant in this gene is also associated with this disease, NBLOSUM = 4.

See unpublished research (below).

Functional 2

A lymphoid cell line with this variant had reduced transferrin receptor numbers and the receptors had lower affinity for transferrin.

See Chitambar CR et al. 2001 (11313265), unpublished research (below).

Case/Control 5

This variant is well established, over 80% of individuals diagnosed with hereditary haemochromatosis are found to be homozygous for this variant.

See Beutler E et al. 2002 (11812557), unpublished research (below).

Familial

This variant is well established.

See unpublished research (below).

 
Clinical importance
Severity 2

Low penetrance for clinical issues, can cause liver and heart problems.

See Beutler E et al. 2002 (11812557), unpublished research (below).

Treatability 3

Phlebotomies may be used to reduce iron load as required.

See unpublished research (below).

Penetrance 1

Beutler et al. implies a penetrance of less than 1%

See Beutler E et al. 2002 (11812557).

 

Impact

Low clinical importance, pathogenic

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

Inheritance pattern

recessive

Summary of published research, and additional commentary

Currently, no test can predict whether a p.C282Y homozygote will develop clinical signs and symptoms. Serum ferritin concentration must be determined to establish disease status and prognosis.

Allele frequency

  • A @ chr6:26093141: 4.9% (532/10758) in EVS
  • A @ chr6:26201119: 2.3% (3/128) in GET-Evidence
  • Frequency shown in summary reports: 4.9% (532/10758)

Publications
 

Chitambar CR, Wereley JP. Iron transport in a lymphoid cell line with the hemochromatosis C282Y mutation. Blood. 2001 May 1;97(9):2734-40. PubMed PMID: 11313265.

From the abstract: “Transferrin receptor (TfR) number was 2- to 3-fold greater in WT cells than in C282Y cells, while TfR affinity for transferrin (Tf) was slightly lower in C282Y cell.”

Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002 Jan 19;359(9302):211-8. PubMed PMID: 11812557.

To determine the penetrance of hereditary haemochromatosis in people homozygous for the C282Y variant, this study screened 41,038 individuals and gathered information on symptoms through laboratory data and questionnaire. They find that while these individuals have significantly higher transferrin saturation, there is low penetrance for reported symptoms. They state that “no symptoms were significantly more common in patients with haemochromatosis genotypes than in controls”. Of 152 homozygotes, they report than only one had signs and symptoms that would suggest a diagnosis of haemochromatosis.

Valenti L, Valenti G, Como G, Santorelli G, Dongiovanni P, Rametta R, Fracanzani AL, Tavazzi D, Messa PG, Fargion S. HFE genotype influences erythropoiesis support requirement in hemodialysis patients: a prospective study. Am J Nephrol. 2008;28(2):311-6. Epub 2007 Nov 16. PubMed PMID: 18025780.

 

Genomes
 

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het A @ chr6:26093141

 

 

 

NA12878

 

Other external references
 

    dbSNP
  • rs1800562
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [epoetin alfa]
    HFE variants, HFE: His63Asp and HFE: Cys282Tyr, reduce the amount of r-HuEPO and iron necessary to support erythropoiesis in hemodialysis patients.
    www.ncbi.nlm.nih.gov/pubmed/18025780
    PolyPhen-2
  • Score: 1.0 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

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