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Hereditary Hemochromatosis, HFE Variant Analysis, Varies
MessageGENETICS TEST INFORMATION
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.
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.
Test Code
HFEGN
Alias/See Also
Epic: LAB833
Mayo: HFET
C282Y
H63D
Hereditary Hemochromatosis
HFE Gene
HFET
HHEMO
HLA-H Gene
Mayo: HFET
C282Y
H63D
Hereditary Hemochromatosis
HFE Gene
HFET
HHEMO
HLA-H Gene
Preferred Specimen
Submit only 1 of the following specimens:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Any anticoagulant
Specimen Volume: 2.5 mL
Collection Instructions:
- Invert several times to mix blood.
- Send whole blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 14 days
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 30 days
Additional Information: Due to lower concentration of DNA yielded from saliva, it is possible that additional specimen may be required to complete testing.
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.
Minimum Volume
0.5 mL
Reject Criteria (Eg, hemolysis? Lipemia? Thaw/Other?)
All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.
Methodology
Droplet Digital Polymerase Chain Reaction (ddPCR)
Setup Schedule
Monday through Friday
Report Available
6 to 7 days
Limitations
CAUTIONS
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.
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.
Reference Range
REFERENCE VALUES
An interpretative report will be provided.
INTERPRETATION
An interpretive report will be provided.
For more information see Hereditary Hemochromatosis Algorithm
For more information see Hereditary Hemochromatosis Algorithm
Clinical Significance
USEFUL FOR
Establishing or confirming the clinical diagnosis of hereditary hemochromatosis (HH) in adults
Testing of individuals with increased transferrin-iron saturation in serum and serum 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
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.
TESTING ALGORITHM
For more information see Hereditary Hemochromatosis Algorithm
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.(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 and compound heterozygosity for the C282Y and H63D variants.(1) 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 a C282Y variant account for 60% to 90% of all HH cases, however clinical penetrance is incomplete.(3) Up to 50% of individuals homozygous for a 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 there is no test that can predict whether a C282Y homozygote 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. Compound heterozygotes for C282Y/H63D have higher penetrance 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 wild-type 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.
Establishing or confirming the clinical diagnosis of hereditary hemochromatosis (HH) in adults
Testing of individuals with increased transferrin-iron saturation in serum and serum 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
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.
TESTING ALGORITHM
For more information see Hereditary Hemochromatosis Algorithm
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.(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 and compound heterozygosity for the C282Y and H63D variants.(1) 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 a C282Y variant account for 60% to 90% of all HH cases, however clinical penetrance is incomplete.(3) Up to 50% of individuals homozygous for a 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 there is no test that can predict whether a C282Y homozygote 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. Compound heterozygotes for C282Y/H63D have higher penetrance 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 wild-type 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.
Performing Laboratory
Mayo Clinic Laboratories - Rochester
3050 Superior Drive NW
Rochester, MN 55901
Last Updated: June 12, 2023
Last Review: N. Wolford, June 12, 2023