Methylene tetrahydrofolate reductase is an enzyme involved directly, and indirectly, in folate and homocysteine metabolism. The (thermolabile) c.677C>T MTHFR polymorphism is present in the homozygous form in 5-15% of the general population. Individuals who are homozygous for the c.677C>T MTHFR variant may have mild elevations in blood homocysteine levels, especially in the setting of inadequate folate intake. Elevated homocysteine is an independent risk factor for venous thromboembolism. Approximately 20% of the population are compound heterozygotes for both MTHFR polymorphisms. Less is known about the thrombotic risk associated with 1298 A>C. The presence of other predisposing risk factors for thrombosis in addition to elevated homocysteine is considered synergistic. The c.677C>T variant is also associated with methotrexate toxicity.