The methylenetetrahydrofolate reductase (MTHFR) enzyme plays a major role in folate metabolism and methylcobalamin regeneration. This enzyme is associated with the gene MTHFR in which specific point mutations result in a variant thermolabile enzyme with reduced activity for the remethylation of homocysteine. Therefore, MTHFR gene variants that reduce MTHFR enzyme function may predispose one to impaired folate metabolism and ultimately mild to moderate hyperhomocysteinemia. In turn, individuals with hyperhomocysteinemia may be at an increased risk for venous thromboembolism. Also, when hyperhomocysteinemia is seen along with a thrombophilia such as factor V Leiden or a factor II mutation, the risk for thrombosis may be compounded.

The two most common genetic variations in the MTHFR gene are p.C677T and p.A1298C. Homozygosity for the MTHFR C677T and A1298C genetic variants is present in 10-16% and 4-6%, respectively, of the Caucasian population in the United States and Europe.

Homozygosity for the p.C677T mutation predisposes individuals to mild hyperhomocysteinemia, usually in the setting of suboptimal serum concentrations of folate. The p.A1298C mutation in the heterozygous state results in decreased MTHFR activity, which is more pronounced in homozygotes; however this particular mutation is not associated with increased plasma homocysteine or folate levels as observed in individuals with the C677T mutation. This assay tests for both mutations. Furthermore, molecular testing of additional genes associated with thrombotic risk, including factor II (prothrombin) and factor V Leiden, is also available at the Genetics Center Molecular Diagnostic Laboratory.