Also Known As
MTHFR DNA Testing
Formal Name
Methylenetetrahydrofolate Reductase Mutations, C677T and A1298C
This article was last reviewed on
This article waslast modified on November 5, 2017.
At a Glance
Why Get Tested?

To evaluate the cause of elevated homocysteine levels; sometimes to help determine your risk of thrombosis or premature cardiovascular disease (CVD)

When To Get Tested?

When you have elevated homocysteine levels; sometimes when a close relative has MTHFR gene mutations or has developed CVD or thrombosis at an early age

Sample Required?

A blood sample drawn from a vein in your arm

Test Preparation Needed?

None

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Lab Tests Online is an award-winning patient education website offering information on laboratory tests. The content on the site, which has been reviewed by laboratory scientists and other medical professionals, provides general explanations of what results might mean for each test listed on the site, such as what a high or low value might suggest to your healthcare practitioner about your health or medical condition.

The reference ranges for your tests can be found on your laboratory report. They are typically found to the right of your results.

If you do not have your lab report, consult your healthcare provider or the laboratory that performed the test(s) to obtain the reference range.

Laboratory test results are not meaningful by themselves. Their meaning comes from comparison to reference ranges. Reference ranges are the values expected for a healthy person. They are sometimes called "normal" values. By comparing your test results with reference values, you and your healthcare provider can see if any of your test results fall outside the range of expected values. Values that are outside expected ranges can provide clues to help identify possible conditions or diseases.

While accuracy of laboratory testing has significantly evolved over the past few decades, some lab-to-lab variability can occur due to differences in testing equipment, chemical reagents, and techniques. This is a reason why so few reference ranges are provided on this site. It is important to know that you must use the range supplied by the laboratory that performed your test to evaluate whether your results are "within normal limits."

For more information, please read the article Reference Ranges and What They Mean.

What is being tested?

The methylenetetrahydrofolate reductase (MTHFR) gene contains the DNA code to produce the MTHFR enzyme. This test detects two of the most common mutations.

When there are mutations or variations in the MTHFR gene, it can lead to serious genetic disorders such as homocystinuria, anencephaly, spina bifida, and others. The MTHFR enzyme is critical for metabolizing one form of B vitamin, folate, into another. It is also part of the process that converts homocysteine into methionine, an important building block for many proteins.

If someone has increased levels of homocysteine, that means the body is not processing it properly. One cause of that could be a mutation in the MTHFR gene, causing homocystinuria. While at least seven unique MTHFR mutations have been found in people with homocystnuria, there are two relatively common DNA sequence variants, known as single nucleotide polymorphisms (SNPs) that are tested. The two MTHFR variants are called C677T and A1298C, and individuals can inherit one or both variants. These SNPs result in changes in the DNA (or mutations) that are associated with increased homocysteine levels in the blood, which may increase the risk of premature cardiovascular disease (CVD), formation of inappropriate blood clots (thrombosis), and stroke.

Approximately 5-14% of the U.S. population is homozygous for C677T, meaning that they have two copies of it. There is some ethnic variability in the frequency, with the highest being in those of Mediterranean ancestry and the lowest in those of African ancestry.

The C677T variant results in a less active form of the MTHFR enzyme and reduced ability to process folate and homocysteine. When a person has two copies of the MTHFR C677T gene mutation (homozygous) or one copy of MTHFR C677T and one copy of A1298C (compound heterozygous), decreased MTHFR enzyme activity slows down the homocysteine-to-methionine conversion process and can lead to a buildup of homocysteine in the blood.

The increase in homocysteine is often mild to moderate but will vary from person to person depending upon the amount of MTHFR enzyme activity. Even if a person has two copies of the MTHFR mutation, that person may not develop high homocysteine levels since adequate folate intake can "cancel out" the effect of the MTHFR mutation.

Results of some studies suggest that high levels of homocysteine in the blood may contribute to risk of CVD by damaging blood vessel walls and promoting formation of plaque (atherosclerosis) and inappropriate blood clots. However, a direct link between homocysteine levels and cardiovascular disease or thrombotic risk has not been found. For more on this, see the article on Homocysteine.

How is the sample collected for testing?

A blood sample is obtained by inserting a needle into a vein in the arm.

Is any test preparation needed to ensure the quality of the sample?

No test preparation is needed.

Accordion Title
Common Questions
  • How is it used?

    The methylenetetrahydrofolate reductase (MTHFR) mutation test is used to detect two relatively common mutations in the MTHFR gene that are associated with elevated levels of homocysteine in the blood. It is not routinely ordered.

    This test is sometimes ordered as a follow-up to an elevated homocysteine test and may be occasionally ordered along with other cardiac risk tests if a person has a personal or family history of premature cardiovascular disease (CVD) or inappropriate blood clots (thrombosis). However, its utility for assessing risk of CVD has not been established and some expert guidelines do not recommended it for thrombosis screening.

    It may be ordered if a person has a close relative with known MTHFR genetic mutations, particularly if that person also has elevated homocysteine levels. MTHFR C677T and A1298C gene mutations are the most common and the ones that are typically tested. If someone has a different mutation in their family, then that specific mutation should be tested.

    An MTHFR test may sometimes be ordered along with other inherited clotting risk tests, such as Factor V Leiden or prothrombin 20210 mutation tests to help evaluate a person's overall risk of developing inappropriate blood clots.

    Although the MTHFR mutation test may be used to help determine the cause of elevated homocysteine, the value of measuring homocysteine levels is not clear. While evidence from some studies suggests that elevated homocysteine levels contribute to the risk of CVD and/or thrombosis, a direct link has not been established. Routine testing for homocysteine levels as a cardiac risk marker is not recommended by the American Heart Association. The College of American Pathologists and the American College of Medical Genetics recommend against testing for the C677T variant, citing limited utility for patients with blood clots. Furthermore, use of homocysteine levels for the purpose of determining risk of CVD, peripheral vascular disease, and stroke is in doubt at this time given that several studies show no benefit or risk reduction in people who were treated with folic acid and vitamin B supplements that lowered their homocysteine level.

  • When is it ordered?

    The MTHFR mutation test may sometimes be ordered when a person has elevated homocysteine levels, especially when the person has a personal or family history of premature cardiovascular disease or thrombosis. It may sometimes be ordered when a close relative has MTHFR gene mutations, although it may not be useful if that relative has normal homocysteine levels, and some laboratories and organizations recommend against using it for thrombophilia screening.

  • What does the test result mean?

    Results typically are reported as negative or positive and, if positive, the report will name the mutation(s) present. Often, an interpretation of the results is also provided.

    Only a small percentage of cases of elevated homocysteine are due to an inherited cause. Of these, MTHFR C677T and A1298C mutations are among the most common.

    If a person has two copies (homozygous) of MTHFR C677T, or has one copy of C677T and one of A1298C, then it is likely that elevated homocysteine levels are due to these inherited mutations, or that the mutations are contributing to them.

    Two copies of A1298C are not typically associated with increased homocysteine levels.

    If the MTHFR mutation test is negative, then the C677T and A1298C mutations were not detected and the tested person's elevated homocysteine level is likely due to another cause. Other, more rare MTHFR genetic mutations will not be detected with typical testing.

    Those with MTHFR mutations and other clotting risk factors, such as Factor V Leiden or PT 20210 mutations, may be at an increased risk of thrombosis.

  • Is there anything else I should know?

    People who have elevated homocysteine levels may be at an increased risk of developing premature cardiovascular disease (CVD) and/or thrombosis, but many, including those with MTHFR mutations, will never develop CVD or thrombosis. The role of homocysteine in cardiac risk assessment is still in the process of being determined.

    Besides MTHFR mutations, there are other causes of elevated homocysteine levels, including deficiency of vitamins B6, B12, and/or folate; these vitamins are required for homocysteine metabolism. The MTHFR mutation may not be present with these acquired, as opposed to inherited, causes of elevated homcysteine. Additionally, if a more rare mutation of MTHFR is causing elevated homocysteine levels, the C677T and A1298C tests will not detect those other mutations.

    For MTHFR mutations, the C677T variant results in substitution of the amino acid alanine for valine. The A1298C variant results in an alanine substitution (versus a gultamine). The C677T valine substitution results in a less active form of the MTHFR enzyme.

    Some studies have shown links between MTHFR genetic mutations and an increased risk of neural tube defects, pre-eclampsia, and certain cancers, but the test is not used clinically with these conditions.

    The MTHFR enzyme is involved in folate metabolism. Because of this, those who have MTHFR mutations and take drugs that affect folate metabolism, such as methotrexate, may be more likely to experience toxicity. An MTHFR mutation test may be performed for a person who is prescribed methotrexate in order to adjust dosages and reduce risk of toxicity.

  • Who performs MTHFR testing?

    It is not offered in every laboratory. In most cases, your blood will be sent to a reference laboratory for testing.

  • Can my MTHFR genes change?
    No, you inherit a copy of the gene from each of your parents and they will not change over time.
  • If I have the same MTHFR gene mutations as a relative, why is my homocysteine level significantly different?

    Even when two people have the same MTHFR mutations, the results and their risks are often different. Many things can affect homocysteine levels, including MTHFR enzyme activity, folate levels, and a person's health status.

View Sources

Sources Used in Current Review

(Reviewed 2011 July). MTHFR. Genetics Home Reference. Available online at http://ghr.nlm.nih.gov/gene/MTHFR through http://ghr.nlm.nih.gov. Accessed February 2014.

(© 1995-2014). 5,10-Methylenetetrahydrofolate Reductase C677T, Mutation, Blood. Mayo Medical Laboratories. Available online at http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/81648 through http://www.mayomedicallaboratories.com. Accessed February 2014.

(© 2014). Methylenetetrahydrofolate Reductase (MTHFR) 2 Mutations 0055655. ARUP Laboratories Laboratory Test Directory. Available online at http://ltd.aruplab.com/Tests/Pub/0055655 through http://ltd.aruplab.com. Accessed February 2014.

Wang W. et al. (2013 March 11). MTHFR C677T Polymorphism and Risk of Congenital Heart Defects: Evidence from 29 Case-Control and TDT Studies. PLOS One. DOI: 10.1371/journal.pone.0058041. Available online at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0058041 through http://www.plosone.org. Accessed February 2014.

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Cohen D.A., et al. (29 November 2013). Laboratory informatics based evaluation of methylene tetrahydrofolate reductase C677T genetic test overutilization. Journal of Pathology Informatics. doi: 10.4103/2153-3539.122389. Available online at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869957/ through http://www.ncbi.nlm.nih.gov. Accessed February 2014.

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Sources Used in Previous Reviews

Mandava, P, et. al. (Updated 2009 May 25). Metabolic Disease and Stroke - Homocystinuria/Homocysteinemia. eMedicine [On-line information]. Available online at http://emedicine.medscape.com/article/1162007-overview through http://emedicine.medscape.com. Accessed October 2010.

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