This page contains advice regarding the common polymorphisms 677C>T and 1298A >C in the MTHFR gene.
Prevelance
The MTHFR 677C>T and 1298A>C polymorphisms are common in the general population - 60–70% of individuals will have at least one of these variants. Overall, 10% of the population will be homozygous or compound heterozygous for these two polymorphisms.
The MTHFR gene encodes an enzyme, which converts homocysteine to methionine. Genetic variations in MTHFR can lead to impaired function of this enzyme, which may result in mild increased homocysteine levels, particularly in individuals who are folate deficient. However, the health implications of this remain unclear.
Research studies
There have been many studies exploring the relationship between MTHFR variants and a multitude of health disorders.
A modest positive association has been found between the MTHFR 677C>T variant and many different medical polygenic disorders including thromboembolic disease, stroke, aneurysms, peripheral artery disease, migraine, hypertension, recurrent pregnancy loss, male infertility, risk for offspring with neural tube defect, certain cancers, neuropsychiatric disease and chemotherapy toxicity in cancer patients. . However, these polymorphisms do NOT result in the classical MTHFR deficiency and are NOT causally linked with any other disorder.
Among 677C>T homozygotes, who have demonstrable elevation in homocysteine levels, there may be a slightly increased risk of venous thrombosis and recurrent pregnancy loss. However, the absolute risk increase is small, and the American College of Medical Genetics (ACMG) currently do NOT recommend MTHFR testing as part of the clinical evaluation of thrombophilia or recurrent pregnancy loss.
Some studies have also suggested that women who are 665C>T homozygotes are at increased risk of having a child with a neural tube defect, particularly if the baby is also a 665C>T homozygote. However, again, the absolute increase is small. At present, pregnant women who carry the variants described, are recommended to take the standard dose of folic acid (in the absence of any other indication for high dose folic acid). Substituting with other folates, such as 5-MTHF, is NOT recommended.
Genetic testing
Genetics laboratories in the NHS generally do not offer diagnostic testing for these polymorphisms, even though a number of private companies have these polymorphisms on their test panels. As per the American College of Medical Genetics and Genomics Practice Guidelines, 2013, there is no evidence of any clinical utility in testing for the 665C>T MTHFR variant or 1286A>C polymorphisms.
Based on our current knowledge, we are unable to add any clinically useful and medically actionable information in such cases.
Overall, we would reassure patients who carry these common variants that this is extremely common in the general population, and based on the scientific evidence currently available, we would not expect this to have significant implications for their health. Furthermore, we would not recommend any specific treatments or supplements.
Homocysteine levels
Please note that these common MTHFR variants/polymorphisms would not be associated with very high homocysteine levels. If your patient has very high homocysteine levels and/or other features suggestive of Homocystinuria, then they may need referral to an appropriate specialty (e.g. Clinical Biochemistry or Adult Metabolic Service).
However, if you still feel that your patient possibly has a genetic disorder or may benefit by being seen in our department, please do not hesitate to discuss this directly with us.