Methylenetetrahydrafolate Reductase (MTHFR) C667T AND A1298C Mutations

BACKGROUND INFORMATION: Methylenetetrahydrafolate Reductase (MTHFR) mutations are associated with increased risk of arterial and venous thrombosis and atherosclerosis due to increased plasma levels of homocysteine.  The expression of MTHFR mutations is impacted by elevated homocysteine levels that may be hereditary (due to mutations in these pathways) or acquired (due to deficiencies of vitamins B12, B6, or folate, renal failure, carcinoma, hypothyroidism, or medications). MTHFR mutations may interact with other inherited risk factors for thrombosis (e.g. factor V Leiden), however, coinheritance does not further increase the thrombotic risk associated with factor V Leiden.

INCIDENCE: Approximately 30-40 percent of Caucasians and 1.4 percent of African Americans are heterozygotes for C677T; C677T homozygosity is seen in 5 percent of Dutch and Finnish populations and 12-15 percent of other European populations. The A1298C mutation had an allelic frequency of 33 percent in the United States.

INHERITANCE: Incomplete penetrance autosomal dominant

PENETRANCE: C677T homozygosity is associated with intermediate and mild hyperhomocysteinemia and a 3 fold increase in premature cardiovascular disease. A1298C homozygosity for A1298C does not raise homocysteine levels or risk for premature cardiovascular disease. Compound heterozygosity (C677T/A1298C) is associated with increased homocysteine plasma levels, but it is unknown at this time if it increases the risk for premature cardiovascular disease. Heterozygosity for C677T or A1298C mutation does not increase the risk for premature cardiovascular disease.


  • CAUSE: Both mutations are a single base pair substitutions MTHFR 677C>T and 1298A>T.
  • NOTE: Standardized nomenclature for the MTHFR mutations are c.677C>T and 1298A>T.
  • CLINICAL SENSITIVITY AND SPECIFICITY: 92 and 91 percent, respectively.
  • METHODOLOGY: Polymerase chain reaction and fluorescence monitoring.
  • LIMITATIONS:  Rare diagnostic errors can occur due to primer site mutations. MTHFR gene mutations, other than C677T and A1298C, will not be detected.
  • The performance characteristics of this test were verified by Delta Pathology MDx.  The U.S. Food and Drug Administration (FDA) has approved this test for clinical use.
  • Counseling and informed consent are recommended for genetic testing.