MTHFR gene variant

Having two copies of A1298C is not associated with significant health risks. We recommend that you discuss this with your doctor to determine if further testing is recommended.

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.

The American Heart Association recommends against testing for the common MTHFR gene variants or homocysteine as a screen for increased risk of cardiovascular conditions. 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.

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.

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.

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.

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

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

Most women with antithrombin deficiency have successful pregnancy outcomes, however studies have shown that they are at an increased (31-49%) risk for blood clots during and following pregnancy. They are also slightly more likely to suffer pregnancy loss without treatment than women without the deficiency (risk for pregnancy loss is around 19%, in comparison women without the deficiency have a 12% risk). Having a single MTHFR gene mutation is not associated with significant increased pregnancy risks, however having two MTHFR gene mutations, or having combined genetic risk factors (e.g., MTHFR and antithrombin deficiency) may add to overall risk. Unfortunately it is very difficult to calculate these specific risks. For women with inherited thrombophilias (like antithrombin deficiency), many recommend the use of low molecular weight or unfractionated heparin during pregnancy and for at least six weeks following delivery to manage clot risks.

The advocacy and support group, Clot Connect summarizes the treatment guidelines for pregnant women with thrombophilia at the following link:

Pregnancy and Blood Clots: Prevention, Diagnosis, Treatment (Clot Connect)

Solitary kidney may occur as a result of kidney donation, medical treatment, or due to a congenital birth defect. Having solitary kidney as a result of kidney donation is associated with an increased risk for high blood pressure (preeclampsia) during pregnancy, but maternal and fetal outcomes are comparable to women with two kidneys. It is not clear if and if so how preeclampsia risk might complicate thrombophilia related risks. Risks for pregnancy complications in women with a history of medical treatment resulting in solitary kidney or congenital absence of one kidney will vary from case to case. Women who are born with a single kidney should be evaluated for anatomical differences of their internal reproductive tract. Around 30% of women born with a single kidney have abnormalities of the reproductive tract, the presence of which may affect fertility and pregnancy outcomes.

Further information on solitary kidney is available at the following Web site:

Solitary Kidney (Kidney & Urology Foundation of America, Inc)

We strongly recommend that you talk to your doctor regarding a referral to a Maternal Fetal Medicine (MFM) specialist. MFM doctors are high-risk pregnancy experts, and are often involved in the care of women with thrombophilias and other medical conditions. The Society for Maternal-Fetal Medicine offers the following tool for finding MFMs in your area:

Find an MFM Specialist (Society for Maternal- Fetal Medicine)

The following support groups are a source for further information and support:

Clot Connect
Campus Box 7305
Mary Ellen Jones Bldg, Room 318
116 Manning Dr.
Chapel Hill, NC 27599
Telephone: 919-966-2809
E-mail: http://www.clotconnect.org/about-clot-connect/contact-u
Website: http://www.clotconnect.org

National Blood Clot Alliance
110 North Washington Street
Suite 328
Rockville, MD 20850
Toll-free: 877-466-2568
Telephone: 301-825-9587
E-mail: info@stoptheclot.org
Website: http://stoptheclot.org

Sidelines High Risk Pregnancy Support
P. O. Box 1808
Laguna Beach, CA 92652
Toll-free: (888)447-4754 (HI-RISK4)
E-mail: sidelines@sidelines.org
Website: http://www.sidelines.org

MTHFR is a gene. We all carry two copies of MTHFR. MTHFR tells our body how to create an enzyme involved in breaking down the amino acid homocysteine. As is true for any gene, the DNA code of the MTHFR gene can vary. When we identify a part of the sequence that varies, we call it a "variant." Genetic research aims to identify specific variants that cause harm or benefit to health.

There are two MTHFR gene variants, called C677T and A1298C, that have been an active area of study. These variants are common. In America, about 25% of people who are Hispanic, and 10-15% of people who are Caucasian have two copies of C677T.

Studies have found that women with two C677T gene variants have an increased risk for having a child with a neural tube defect. Studies have also found that men and women with two C677T gene variants and elevated homocysteine levels may be at a mild increased risk for blood clots (venous thromboembolism).

Very high homocysteine levels rarely result from having two common variants alone. People with very high homocysteine levels should be carefully evaluated for other factors known to affect homocysteine. Doing so may bring to light dietary deficiencies, thyroid disease, diabetes, high cholesterol, or life- style factors (physical inactivity, smoking and obesity) which can impact homocystine levels. If high levels of homocysteine cannot be explained by these factors, a consultation with a genetics professional may be helpful in identifying rare genetic causes of the high homocysteine. To learn more about rare genetic causes, visit: Homocystinuria due to MTHFR Deficiency.

Having one mutation in the MTHFR gene is typically not associated with an increased risk of blood clots, because it usually does not lead to high levels of homocysteine in the blood.

For more on signs and symptoms associated with MTHFR mutations, visit: http://rarediseases.info.nih.gov/gard/10953/mthfr-gene-mutation/resources/9

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:

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). 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.

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. 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.

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

MTHFR is a part of pathways acted on by certain drugs, making it a gene of research interest. A threshold of evidence must be reached before research data can be used in patient care. The Pharmacogenomics Knowledgebase (PharmGKB) is a NIH-funded resource that can help you gauge the status of current data and locate trustworthy drug dosing guidelines. Visit the PharmGKB MTHFR Summary and PharmGKB MTHFR Clinical Annotation Page. You may need to register to view the pages but registration is free.

Varga E, Sturm A, Moll S. Homocysteine and MTHFR Mutations. Circulation. 2015;132:e6-e9. [PDF]

LabTests Online has information on testing that is related to MTHFR mutation and Homocysteine.