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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.

Reasons for Referral

  • An individual with known mild to moderate hyperhomocysteinemia.
  • An individual known to be heteroyzygous for factor V Leiden or factor II-related (prothrombin) thrombophilia.
  • An individual known to be homozygous for factor V Leiden or factorII (prothrombin)-related thrombophilia.
  • An individual with unprovoked venous thromboembolism (VTE) before the age of 50.
  • An individual with recurrent VTE.
  • An individual with VTE at an unusual site (cerebral, mesenteric, portal, or hepatic veins).

Testing Methods

DNA is isolated and analyzed specifically for the two MTHFR mutations: p.C667T and p.A1298C.

Turn Around Time

6 days or fewer

Specimen Requirements and Shipping/Handling

Blood: A single tube with 1-5 mL whole blood in EDTA (lavender top).

Saliva: To request a DNA Mouthwash Collection Kit please contact Genetics Center at (714)288-3500.


Store blood at 4°C until shipment. Ship at ambient temperature in an insulated container via overnight delivery within 96 hours of collection.

Send Specimen(s) to:

Genetics Center
211. S Main Street
Suite AA
Orange, CA 92868
Tel: (714)288-3500


CPT Codes

CPT’s: 81291×2, G0452

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