MTHFR gene variant

People with common MTHFR variants can have normal or elevated levels of homocysteine in their blood or urine. MTHFR variants and elevated homocysteine levels have been studied as risk factors for a number of health conditions.

When thinking about risk factors it is important to not only think about if the variants put you at risk for a condition, but if so, how much risk. You will find many studies on MTHFR and health risks. For most of these, evidence is lacking regarding an association.^[6] Described below are conditions that are more widely recognized to be associated with the common MTHFR variants.

Studies suggest that women with two C677T gene variants are twice as likely to have a child with a neural tube defect.^[4] However, because neural tube defects are rare, their actual risk is still far less than 1% (0.14%).^[7][8] You can learn more about neural tube defects and health risks by visiting the March of Dimes Web site.

Studies have also found that men and women with two C677T gene variants and elevated homocysteine levels may be at a mildly increased risk for blood clots (venous thromboembolism).^[4]

Risks associated with having one C677T and one A1298C is the same, or possibly slightly lower than, that of having two C677T gene changes.^[9][4]

For the vast majority of people the overall risk associated with the common MTHFR variants is small. So small, that having them does not change treatment. This is why testing for the variants is not recommended, unless a person has very high homocysteine levels. It is important to keep in mind that neural tube defects and blood clots have many other risk factors.

Very high homocysteine levels rarely result from having the common variants alone. People with very high homocysteine levels should be carefully evaluated for other factors known to affect homocysteine, such as:^[10][11][12]

Low thyroid hormones (hypothyroidism)
Chronic conditions (obesity, diabetes, high cholesterol, physical inactivity, high blood pressure)
Medications (atorvastatin, fenofibrate, methotrexate, andnicotinic acid)
Smoking
Advanced age

High homocysteine levels can also result from dietary deficiencies of folate, vitamin B6, and vitamin B12. It is very important to diagnose vitamin B12 deficiencies, as high dose folic acid supplements can mask B12 deficiencies, and put people at risk for serious and irreversible symptoms. Learn more about B12 deficiency.

If high levels of homocysteine can not be explained by factors such as those listed above, a consultation with a genetics professional may be helpful in identifying rare genetic causes of the high homocysteine.^[5] To learn more about rare genetic causes, visit: Homocystinuria due to MTHFR Deficiency.

Because each person has two copies of the MTHFR gene, people can inherit one copy of a MTHFR gene variant or two copies of it (one from each parent). People who inherit two copies of C677T have a higher risk for having a child with a neural tube defect. Having two C677T variants and elevated homocysteine levels may cause a slightly higher risk for blood clots.^[9] 

Risks associated with having one C677T and one A1298C is the same, or possibly slightly lower than, that of having two C677T gene changes.^[9][4]

Rare MTHFR gene variants can lead to homocystinuria, which is inherited in an autosomal recessive manner.^[13] Visit our "Homocystinuria due to MTHFR deficiency" webpage.

Genetic testing is available for MTHFR gene variants, however testing is rarely recommended.

The American Congress of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics recommends against testing for common MTHFR gene variants. Common MTHFR gene variants have not been proven to be a concerning risk factor for blood clots, pregnancy loss, or other negative pregnancy outcomes.^[14]

The American Heart Association recommends against testing for the common MTHFR gene variants or homocysteine as a screen for increased risk of cardiovascular conditions.^[15][9][14] The Association does not consider MTHFR a major risk factor for heart disease.

The College of American Pathologists, the American College of Medical Genetics, and the American Heart Association recommend against testing for C677T and A1298C in people with blood clots. This is because results have little impact on a persons medical management.^[15][9][4]

Some people who contact GARD have already had testing for MTHFR gene variants and want to know if the variants could be causing their symptoms. Any individual who suspects that a disease or disorder is related to MTHFR deficiency should talk to their doctor about testing for fasting homocysteine levels in the blood.^[4]

If the fasting blood homocysteine level is high, then the patient should seek medical advice from an expert doctor in this field who can address the possible medical implications. If the fasting homocysteine level in the blood is normal, then it is unlikely that the person's symptoms are due to the MTHFR genetic variation.

Having MTHFR gene variants alone does not impact treatment. If a person has high homocysteine levels they should be carefully evaluated to identify all causes. Very high homocysteine levels rarely result from having the common variants alone. People with very high homocysteine levels should be carefully evaluated for other factors known to affect homocysteine, such as:^[10][11][12]

Low thyroid hormones (hypothyroidism)
Chronic conditions (obesity, diabetes, high cholesterol, physical inactivity, high blood pressure)
Medications (atorvastatin, fenofibrate, methotrexate, andnicotinic acid)
Dietary deficiencies (folate, vitamin B6, vitamin B12)
Smoking
Advanced age

Treatments and life-style changes are given based upon the patient's circumstances. As mentioned above, homocysteine levels can rise in people with and without MTHFR gene variants if they lack folate, choline, or B vitamins (B12, B6, and riboflavin).^[10][11] It is very important to diagnose vitamin B12 deficiencies, as high dose folic acid supplements can mask B12 deficiencies, and put people at risk for serious and irreversible symptoms. Visit the Office of Dietary Supplements Web page for more on B12. People with concerns about their nutrition should speak with a healthcare professional. Supplements may be recommended if the person is found to have a nutritional deficiency.^[3][10]

Current clinical guidelines do not recommend changes in prenatal care or prenatal vitamins based upon MTHFR gene variant status alone. Women of childbearing age should take the standard dose of folate supplementation to reduce the risk of neural tube defects.^[4][14][16] Women with a previous child with a neural tube defect or a family history of neural tube defect should talk to their doctors about requirements for extra folate supplementation.^[14]

We recommend you speak with a trusted healthcare professional before taking any supplement.