MTHFR Gene: Variants, Testing and What Your DNA Can Tell You

Short answer: MTHFR is a gene that makes an enzyme used in folate metabolism. Two common variants, C677T and A1298C, lower how well that enzyme works, but they are common and are not a diagnosis. Medical guidelines advise against routine testing for these variants to assess clotting risk or pregnancy loss.

Key Takeaways

• C677T and A1298C are common polymorphisms in the general population, not rare mutations.
• Lower enzyme activity is not a diagnosis. Two copies of C677T can raise homocysteine mildly, mainly when folate intake is low.
• The American College of Medical Genetics and Genomics (ACMG) says MTHFR polymorphism testing has minimal clinical use and should not be part of a routine thrombophilia evaluation.
• Your DNA data can show which MTHFR variants you carry. To read the letters correctly, you need to know which DNA strand your file reports.

What Is the MTHFR Gene?

The MTHFR gene provides instructions for making methylenetetrahydrofolate reductase, an enzyme that helps the body process folate (vitamin B9). Everyone has two copies of the gene, one from each parent.

The enzyme produces 5-methyltetrahydrofolate, which the body uses to recycle the amino acid homocysteine back into methionine.

The Two Common MTHFR Variants

Both variants are common in the general population, and both are linked to lower enzyme activity.

• C677T (rs1801133): replaces alanine with valine in the enzyme (p.Ala222Val). In Genome Explorer it appears as G>A on chromosome 1, position 11,796,321 (GRCh38).
• A1298C (rs1801131): replaces glutamate with alanine in the enzyme. In Genome Explorer it appears as T>G.

Older articles use the historical names 677C>T and 1298A>C. Because the gene is read from the opposite strand, Genome Explorer shows the same changes as G>A and T>G. Our bioinformatics team's article Why MTHFR C677T can be hard to find in Genome Explorer explains the naming in detail.

What Do Medical Guidelines Say About MTHFR Testing?

The medical position on routine testing is consistent across several sources.

• ACMG (2013). The ACMG practice guideline concluded that MTHFR polymorphism testing has minimal clinical use and should not be ordered as part of a routine evaluation for thrombophilia. It also advises against ordering genotyping for at risk family members.
• Thrombosis specialists (2022). A call to action in Research and Practice in Thrombosis and Haemostasis noted that guidelines from ACMG, ACOG, the British Society for Haematology, the Society for Maternal-Fetal Medicine and Choosing Wisely all agree that MTHFR testing should not be performed to evaluate thrombosis, and urged laboratories to remove it from thrombophilia panels.

MTHFR and Homocysteine

Some people with two copies of C677T have mildly higher homocysteine, mostly when their folate intake is low. Elevated homocysteine was once thought to raise the risk of heart disease and blood clots, which is why MTHFR testing became common. The ACMG guideline reports that later meta-analyses did not support an association between high homocysteine and coronary heart disease, or between MTHFR variant status and venous thromboembolism.

If you want to know your homocysteine level, a blood test measures it directly.

Folic Acid and MTHFR Variants

The CDC states that people with an MTHFR variant can process all types of folate, including folic acid, and that common variants such as C677T are not a reason to avoid folic acid. If you could become pregnant, the CDC advises getting 400 mcg of folic acid daily, even if you have an MTHFR variant. Ask your clinician before you change any supplement.

Severe MTHFR Deficiency Is a Different Condition

Severe MTHFR deficiency is a rare inherited disorder caused by much rarer changes in the same gene. It is not the same as carrying C677T or A1298C. Read more in our article on homocystinuria due to MTHFR deficiency.

How to Find Your MTHFR Variants in Your DNA Data

Sequencing reads 100% of your DNA, including over 30,000 genes, so MTHFR is part of your data. Search your file or Genome Explorer for the variant IDs rs1801133 (C677T) and rs1801131 (A1298C).

In Genome Explorer, C677T genotypes appear as GG (no copies, written 677CC in older articles), GA (one copy, 677CT) or AA (two copies, 677TT). The letters differ from older articles because of the strand, but the DNA result is the same. Do not change supplements or medicines based on a raw data result alone.

Related Articles

• Why MTHFR C677T Can Be Hard to Find in Genome Explorer: how the same variant appears under different names.
• MTHFR Thermolabile Polymorphism (C677T): the common variant in more detail.
• Decoding Elevated Homocysteine Levels: how homocysteine is measured and what raises it.
• Homocystinuria due to MTHFR Deficiency: the rare, severe condition.

Get Tested With Whole Genome Sequencing

Whole genome sequencing reads 100% of your DNA, including over 30,000 genes, so the MTHFR gene is part of your data. Sequencing's Kit Bundles include a Whole Genome Sequencing kit and Next Gen Disease Screening, which analyzes your genome for more than 15,000 conditions. Guidelines advise against relying on a common MTHFR variant alone, so bring your results to a clinician.

Shop All Whole Genome Sequencing Kit Bundles

Frequently Asked Questions About the MTHFR Gene

Is an MTHFR variant a disease?

No. C677T and A1298C are common polymorphisms in the general population. They are linked to lower enzyme activity, which is not the same as a diagnosis.

Do I need to be tested for MTHFR?

Major medical groups advise against routine MTHFR testing to evaluate clotting risk. Ask your clinician whether any testing fits your situation.

Should I take methylfolate if I carry an MTHFR variant?

The CDC states that people with an MTHFR variant can process all types of folate, including folic acid. If you could become pregnant, follow standard folic acid guidance of 400 mcg daily. Ask your clinician before you change any supplement.

Can MTHFR variants raise homocysteine?

Two copies of C677T can lead to mildly higher homocysteine, mostly when folate intake is low. A blood test measures homocysteine directly.

Does my raw DNA data show my MTHFR variants?

It can, if your file includes rs1801133 and rs1801131. Sequencing reads 100% of your DNA, so these positions are covered.

Can I inherit MTHFR variants?

Yes. You receive one copy of the gene from each parent, so variants are passed through families.

References

1. Hickey SE, Curry CJ, Toriello HV. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153-156. PubMed 23288205
2. Deloughery TG, Hunt BJ, Barnes GD, et al. A call to action: MTHFR polymorphisms should not be a part of inherited thrombophilia testing. Res Pract Thromb Haemost. 2022;6(4). PMC 9175241
3. National Center for Biotechnology Information. Medical Genetics Summaries, MTHFR (Bookshelf NBK66131). ncbi.nlm.nih.gov/books/NBK66131
4. Centers for Disease Control and Prevention. MTHFR gene variant and folic acid facts. cdc.gov
5. MedlinePlus Genetics. MTHFR gene. medlineplus.gov/genetics/gene/mthfr
6. MedlinePlus. Homocysteine test. medlineplus.gov/lab-tests/homocysteine-test

This article is for education and is not a substitute for professional medical advice, diagnosis, or treatment. Talk to a qualified healthcare provider about your own health.