Test Id : HFET
Hereditary Hemochromatosis, HFE Variant Analysis, Varies
Useful For
Suggests clinical disorders or settings where the test may be helpful
Establishing or confirming the clinical diagnosis of hereditary hemochromatosis (HH) in adults
Testing of individuals with increased serum transferrin-iron saturation and ferritin
Predictive testing of individuals who have a family history of HH, in coordination with appropriate genetic counseling
This test is not recommended for population screening.
Genetics Test Information
Provides information that may help with selection of the correct genetic test or proper submission of the test request
This test detects the 2 common disease-causing variants in the HFE gene: C282Y (c.845G>A) and H63D (c.187C>G). The S65C variant will be reported only when it is observed as part of the C282Y/S65C genotype.
Highlights
Molecular testing can be done to establish or confirm the diagnosis of hereditary hemochromatosis in individuals with clinical symptoms.
This assay will not detect all variants in the HFE gene that cause hereditary hemochromatosis.
Method Name
A short description of the method used to perform the test
Droplet Digital Polymerase Chain Reaction (ddPCR)
NY State Available
Indicates the status of NY State approval and if the test is orderable for NY State clients.
Reporting Name
Lists a shorter or abbreviated version of the Published Name for a test
Aliases
Lists additional common names for a test, as an aid in searching
C282Y
H63D
Hereditary Hemochromatosis
HFE Gene
HFET
HHEMO
HLA-H Gene
HFE HC
Specimen Type
Describes the specimen type validated for testing
Varies
Specimen Required
Defines the optimal specimen required to perform the test and the preferred volume to complete testing
Patient Preparation: A previous bone marrow transplant from an allogeneic donor will interfere with testing. For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube: Lavender top (EDTA) or yellow top (ACD)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA is met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
Specimen Type: Cord blood
Container/Tube: Lavender top (EDTA) or yellow top (ACD)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send cord blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA is met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
3.While a properly collected cord blood sample may not be at risk for maternal cell contamination, unanticipated complications may occur during collection. Therefore, maternal cell contamination studies are recommended to ensure the test results reflect that of the patient tested and are available at an additional charge. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Saliva
Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.
Supplies: Saliva Swab Collection Kit (T786)
Specimen Volume: 1 Swab
Collection Instructions: Collect and send specimen per kit instructions.
Specimen Stability Information: Ambient (preferred) 30 days/Refrigerated 30 days
Additional information: Saliva specimens are acceptable but not recommended. Due to lower quantity/quality of DNA yielded from saliva, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.
Specimen Type: Extracted DNA
Container/Tube:
Preferred: Screw Cap Micro Tube, 2 mL with skirted conical base
Acceptable: Matrix tube, 1 mL
Collection Instructions:
1. The preferred volume is at least 100 mcL at a concentration of 75 ng/mcL.
2. Include concentration and volume on tube.
Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated
Additional Information: DNA must be extracted in a CLIA-certified laboratory or equivalent and must be extracted from a specimen type listed as acceptable for this test (including applicable anticoagulants). Our laboratory has experience with Chemagic, Puregene, Autopure, MagnaPure, and EZ1 extraction platforms and cannot guarantee that all extraction methods are compatible with this test. If testing fails, one repeat will be attempted, and if unsuccessful, the test will be reported as failed and a charge will be applied. If applicable, specific gene regions that were unable to be interrogated due to DNA quality will be noted in the report.
Special Instructions
Library of PDFs including pertinent information and forms related to the test
Forms
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:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing-Spanish (T826)
2. Molecular Genetics: Congenital Inherited Diseases Patient Information (T521)
3. If not ordering electronically, complete, print, and send a Benign Hematology Test Request (T755) with the specimen.
Specimen Minimum Volume
Defines the amount of sample necessary to provide a clinically relevant result as determined by the testing laboratory. The minimum volume is sufficient for one attempt at testing.
See Specimen Required
Reject Due To
Identifies specimen types and conditions that may cause the specimen to be rejected
Specimen Stability Information
Provides a description of the temperatures required to transport a specimen to the performing laboratory, alternate acceptable temperatures are also included
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Varies | Varies | ||
Useful For
Suggests clinical disorders or settings where the test may be helpful
Establishing or confirming the clinical diagnosis of hereditary hemochromatosis (HH) in adults
Testing of individuals with increased serum transferrin-iron saturation and ferritin
Predictive testing of individuals who have a family history of HH, in coordination with appropriate genetic counseling
This test is not recommended for population screening.
Genetics Test Information
Provides information that may help with selection of the correct genetic test or proper submission of the test request
This test detects the 2 common disease-causing variants in the HFE gene: C282Y (c.845G>A) and H63D (c.187C>G). The S65C variant will be reported only when it is observed as part of the C282Y/S65C genotype.
Clinical Information
Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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.(1) The disease is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues (eg, liver, skin, heart, joints). Clinical symptoms of HFE hemochromatosis usually appear in men between age 40 and 60 years and after menopause in women, and they might be affected by other factors such as intake of iron and other mineral supplements, vitamin C, and alcohol consumption. Iron overload can lead to hepatic cirrhosis, hepatocellular carcinoma, diabetes mellitus, arthropathy, and cardiomyopathy. Such complications may be prevented by phlebotomy, and patients may have a normal life expectancy when treated before organ damage occurs.(2) 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 also be performed to confirm/establish the diagnosis.
The two most common variants in the HFE gene are C282Y and H63D. The majority of HH patients (approximately 85-90%) show homozygosity for the C282Y variant or compound heterozygosity for the C282Y and H63D variants.(1) Individuals with carrier status (heterozygotes) generally do not develop complications of iron overload but may have abnormal serum iron results.(1) Furthermore, clinically significant iron overload can also occur in the absence of known HFE variants. Therefore, a negative HFE test does not exclude other rare variants in the HFE gene or in other genes and, thus, does not exclude a diagnosis of iron overload or hemochromatosis.
The most common disease-causing variant identified in the HFE gene is C282Y (c.845G>A in exon 4). Individuals who are homozygous for the C282Y variant account for 60% to 90% of all HH cases, however clinical penetrance is incomplete.(3) Up to 50% of individuals homozygous for C282Y develop iron overload (elevated serum iron indices) and 10% to 33% (mainly men) develop hemochromatosis-related syndromes or end-organ damage symptoms.(2) Currently no test can predict whether an individual who is homozygous for C282Y will develop clinical symptoms. Additionally, 3% to 8% of individuals affected with HH are heterozygous for this variant. These frequencies show variability among different populations, with the highest frequency observed in individuals of Northern European ancestry.
The H63D (c.187C>G in exon 2) variant is also associated with HH; however, the presence of a single H63D variant is unlikely to be of clinical significance in the absence of other disease-causing variants. Additionally, homozygosity for H63D is insufficient to cause clinically significant iron overload in the absence of other modifying risk factors. Individuals who are compound heterozygous for C282Y/H63D have higher penetrance compared to those who are H63D homozygous and have been associated with increased hepatic iron concentrations. Approximately 0.5% to 2% of individuals with this genotype will develop clinical evidence of iron overload.(2) 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).(4)
The clinical significance of a third HFE variant, S65C (c.193A>T in exon 2), appears to be minimal. This rare variant displays a very low penetrance and is generally not associated with iron overload. Individuals who are heterozygous for S65C with either the wildtype or H63D allele do not seem to be at an increased risk for HH. Compound heterozygosity for C282Y and S65C may confer a low risk for mild HH.(1) Therefore, the C282Y/S65C genotype is reported when observed.
For more information see Hereditary Hemochromatosis Algorithm
Reference Values
Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretative report will be provided.
Interpretation
Provides information to assist in interpretation of the test results
The interpretive report includes an overview of the findings as well as the associated clinical significance.
Cautions
Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This assay only tests for the C282Y, H63D and S65C (reported as a part of the C282Y/S65C genotype) variants and will not detect all variants in the HFE gene that may be associated with hereditary hemochromatosis. Therefore, the absence of a detectable C282Y, H63D, or S65C variant does not rule out the possibility that an individual is a carrier of or affected with this disease.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in the interpretation of results may occur if information given is inaccurate or incomplete.
Rare variants (ie, polymorphisms) exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
In rare cases, DNA variants of unknown significance may be identified.
Because of concerns of the overall penetrance of HFE variants, HFE genetic testing is not recommended for population screening.
Clinical Reference
Recommendations for in-depth reading of a clinical nature
1. Barton JC, Edwards CQ. HFE Hemochromatosis. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2000. Updated April 11, 2024. Accessed March 24, 2025. Available at www.ncbi.nlm.nih.gov/books/NBK1440/
2. Kowdley KV, Brown KE, Ahn J, Sundaram V. ACG Clinical Guideline: Hereditary Hemochromatosis. Am J Gastroenterol. 2019;114(8):1202-1218
3. Porto G, Brissot P, Swinkels DW, Zoller H, et al. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH). Eur J Hum Genet. 2016;24(4):479-495
4. Hollerer I, Bachmann A, Muckenthaler MU. Pathophysiological consequences and benefits of HFE mutations: 20 years of research. Haematologica. 2017;102(5):809-817
Method Description
Describes how the test is performed and provides a method-specific reference
Droplet digital polymerase chain reaction (ddPCR) is used to test for the following three variants in the HFE gene: C282Y, H63D, and S65C. Because of the minimal effect on iron metabolism associated with the S65C variant, it is only reported when it is found with the C282Y variant (ie, if the patient has the C282Y/S65C genotype).(Unpublished Mayo method)
PDF Report
Indicates whether the report includes an additional document with charts, images or other enriched information
Day(s) Performed
Outlines the days the test is performed. This field reflects the day that the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time before the test is performed. Some tests are listed as continuously performed, which means that assays are performed multiple times during the day.
Varies
Report Available
The interval of time (receipt of sample at Mayo Clinic Laboratories to results available) taking into account standard setup days and weekends. The first day is the time that it typically takes for a result to be available. The last day is the time it might take, accounting for any necessary repeated testing.
Specimen Retention Time
Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded
Performing Laboratory Location
Indicates the location of the laboratory that performs the test
Fees :
Several factors determine the fee charged to perform a test. Contact your U.S. or International Regional Manager for information about establishing a fee schedule or to learn more about resources to optimize test selection.
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- Prospective clients should contact their account representative. For assistance, contact Customer Service.
Test Classification
Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR) product.
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.
CPT Code Information
Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Clinic Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.
CPT codes are provided by the performing laboratory.
CPT codes are provided by the performing laboratory.
81256-HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (C282Y and H63D)
LOINC® Information
Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the order and results codes of this test. LOINC values are provided by the performing laboratory.
| Test Id | Test Order Name | Order LOINC Value |
|---|---|---|
| HFET | Hereditary Hemochromatosis HFE Test | 34519-9 |
| Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
|---|---|---|
| 614667 | Result Summary | 50397-9 |
| 614668 | Result | 82939-0 |
| 614669 | Interpretation | 69047-9 |
| 614670 | Specimen | 31208-2 |
| 614791 | Source | 31208-2 |
| 614792 | Method | 85069-3 |
| 614793 | Released By | 18771-6 |