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Test ID: HFE Hemochromatosis HFE Gene Analysis, Blood

Useful For

Establishing or confirming the clinical diagnosis of hereditary hemochromatosis (HH) in adults


HFE genetic testing is NOT recommended for population screening


Testing of individuals with increased transferrin-iron saturation in serum and serum ferritin


With appropriate genetic counseling, predictive testing of individuals who have a family history of HH

Testing Algorithm

See Hereditary Hemochromatosis Algorithm in Special Instructions.

Method Name

Polymerase Chain Reaction (PCR)-Based Assay Utilizing Agena Mass Array Platform

Reporting Name

Hemochromatosis HFE Gene Analysis, B

Specimen Type


Shipping Instructions

Specimen preferred to arrive within 96 hours of draw.

Specimen Required

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Specimen Type: Whole blood


Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 2.5 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Minimum Volume

0.5 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Ambient (preferred)

Clinical Information

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism with a carrier frequency of approximately 1 in 10 individuals of northern European ancestry. The disease is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues. Iron overload can cause hepatic cirrhosis, hepatocellular carcinoma, diabetes mellitus, arthropathy, and cardiomyopathy. Such complications can generally be prevented by phlebotomy, and patients have a normal life expectancy if treated before organ damage occurs.

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For individuals with clinical symptoms consistent with HH or biochemical evidence of iron overload, an HH diagnosis is typically based on the results of transferrin-iron saturation and serum ferritin concentration. Molecular testing can be done to confirm the diagnosis.


The majority of HH patients have mutations in the HFE gene. Clinically significant iron overload also can occur in the absence of known HFE mutations, so a negative HFE test does not exclude a diagnosis of iron overload or hemochromatosis.


The most common mutation in the HFE gene is C282Y (exon 4, 845G->A). Homozygosity for the C282Y mutation is associated with 60% to 90% of all cases of HH. Additionally, 3% to 8% of individuals affected with HH are heterozygous for this mutation. These frequencies show variability among different populations, with the highest frequency observed in individuals of northern European ancestry. Penetrance for elevated serum iron indices among C282Y homozygotes is relatively high, but not 100%. However, the penetrance for the characteristic clinical end points (such as diabetes mellitus, hepatic cirrhosis, and cardiomyopathy) is quite low. There is no test that can predict whether a C282Y homozygote will develop clinical symptoms.


The H63D (exon 2, 187C->G) mutation is associated with HH, but the actual clinical effects of this mutation are uncertain. Homozygosity for H63D is insufficient to cause clinically significant iron overload in the absence of additional modifying factors. However, compound heterozygosity for C282Y/H63D has been associated with increased hepatic iron concentrations. Approximately 1% to 2% of individuals with this genotype will develop clinical evidence of iron overload. While individuals with this genotype may have increased iron indices, most will not develop clinical disease without comorbid factors (steatosis, diabetes, or excess alcohol consumption).


The clinical significance of a third HFE mutation, S65C (exon 2, 193A->T), appears to be minimal. This rare variant displays a very low penetrance. Compound heterozygosity for C282Y and S65C may confer a low risk for mild HH. Individuals who are heterozygous for S65C and either the wild-type or H63D alleles do not seem to be at an increased risk for HH. The S65C mutation is only reported when it is part of the C282Y/S65C genotype.


See Hereditary Hemochromatosis Algorithm in Special Instructions.

Reference Values

An interpretative report will be provided.


An interpretive report will be provided.

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For more information about hereditary hemochromatosis testing, see Hereditary Hemochromatosis Algorithm in Special Instructions.

Clinical Reference

1. Mura C, Raguenes O, Ferec C: HFE Mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 1999;93(8):2502-2505

2. Beutler E, Felitti VJ, Koziol J, et al: Penetrance of 845G->A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359(9302):211-218

3. Walsh A, Dixon JL, Ramm GA, et al: The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis. Clin Gastroenterol Hepatol 2006;4(11):1403-1410

4. Whitlock EP, Garlitz BA, Harris EL, et al: Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006;145(3):209-223

Day(s) Performed

Monday through Friday

Report Available

6 to 7 days

Test Classification

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information

81256-HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (eg, C282Y, H63D)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
HFE Hemochromatosis HFE Gene Analysis, B 34519-9


Result ID Test Result Name Result LOINC Value
52899 Result Summary 50397-9
52900 Result 21694-5
52901 Interpretation 69047-9
52902 Specimen 31208-2
52903 Source 31208-2
52904 Method 85069-3
52905 Released By 18771-6


1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Congenital Inherited Diseases Patient Information (T521) in Special Instructions

3. If not ordering electronically, complete, print, and send a Benign Hematology Test Request Form (T755) with the specimen.

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