Methylenetetrahydrofolate Reductase (MTHFR), DNA Analysis

MTHFR DNA analysis tests for the presence or absence of two variants in the MTHFR gene: C677T and A1298C. These variants result in reduced MTHFR enzyme activity. Reduced MTHFR enzyme activity is a genetic risk factor for hyperhomocysteinemia, especially when present with low serum folate levels.¹

Mild to moderate hyperhomocysteinemia was previously thought to be a risk factor for coronary artery disease (CAD) and venous thromboembolism. However, an association between MTHFR variants, hyperhomocysteinemia, and increased risk for thromboembolism is not supported by current literature.¹ Therefore, the utility of MTHFR variant testing in the evaluation of venous thromboembolism and adverse pregnancy outcome is uncertain and is not recommended by the American College of Medical Genetics and Genomics (ACMG) or the American Congress of Obstetricians and Gynecologists (ACOG).¹

Yes. This genetic test is performed by extracting DNA from the patient’s leukocytes and then testing that DNA for the presence or absence of two MTHFR gene variants (C677T and A1298C). Heparin and warfarin are not known to affect this testing methodology.

Question 3. My patient has had recurrent miscarriages. How do I interpret the result of this test in that context?      

The role of MTHFR variants in miscarriage is controversial; most evidence shows that MTHFR variant status does not predict thrombophilia or pregnancy loss in pregnant women.^1,2 Consider investigating the presence or absence of other risk factors.

Question 4. What is the clinical significance of the C677T variant? 

Modest positive association has been found between the C677T variant of the MTHFR gene and many other medical complications, such as recurrent pregnancy loss, risk of offspring with neural tube defects, neuropsychiatric disease, and chemotherapy toxicity. Increased risk of CAD and venous thromboembolism and increased plasma homocysteine can be caused by a variety of genetic and nongenetic factors not screened for by this assay. If indicated by a personal or family history of thromboembolism, consider additional testing such as plasma homocysteine levels and factor V Leiden and prothrombin gene mutations.

The A1298C variant is not associated with a significantly increased risk for CAD, venous thromboembolism, or adverse pregnancy outcome. Increased risk of CAD and venous thromboembolism and increased plasma homocysteine can be caused by a variety of genetic and nongenetic factors not screened for by this assay. If indicated by a personal or family history of thromboembolism, consider additional testing such as plasma homocysteine levels and factor V Leiden and prothrombin gene mutations.