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About MTHFR – Information for GPs

About MTHFR – Information for GPs
(MTHFR = Methylenetetrahydrofolate Reductase)


In summary

  1. MTHFR variants are very common in the general population.
  2. MTHFR variant C677T is considered a strong determinant of folate status in women of reproductive age 1 and has been associated with lower levels of red blood cell folate and elevated homocysteine. MTHFR acts in association with a number of other genes as a threshold risk factor, and is not usually individually significant.
  3. Folic acid supplementation has been shown to increase folate levels, regardless of MTHFR status,  to that which is considered protective for neural tube defects 2.
  4. MTHFR variants are unlikely to have any impact on health in the absence of low red blood cell folate or high homocysteine. 
  5. MTHFR status does not change the recommendation for women to take folic acid supplementation at least 1 month prior to conception, as per general guidelines.



The MTHFR gene encodes an enzyme in the methylation cycle (See Fig 1).

MTHFR (‘5,10-methylenetetrahydrofolate reductase’) converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, and is an important cofactor in the biosynthesis of SAMe (S-adenosyl methionine), the primary methyl donor involved in regulating gene expression.

Fig 1 - The Methylation Cycle:  Taken from


A number of variants have been identified in the MTHFR gene.  The two most commonly reported variants are C677T and A1298C.  These variants are common among the general population.

TABLE 1 - Frequency of MTHFR variants as a percentage of the population3

Having one or both of these variants may reduce a person's ability to metabolise folate.  This does not generally cause health problems if there is sufficient folate through diet or supplementation.  Low folate is unlikely in countries such as Australia that have folic acid fortification programs4 (See table 2 for more details).


There is insufficient evident in the literature at this stage to determine the clinical utility of MTHFR testing. MTHFR gene variants, in combination with other factors, have been associated with an increased risk of developing a number of conditions, such as neural tube defects, cardio vascular disease, cancer, thrombophilia, infertility, autism.  Testing for MTHFR would be considered investigational only.

In summary:

    1. The RACGP does not currently have guidelines for testing MTHFR
    2. There is currently no MBS schedule for MTHFR testing
    3. MTHFR testing as part of an investigation for infertility or as a direct-to-consumer test currently  occurs  in some organisations in NSW
    4. There is some evidence to consider MTHFR in the event of:
      • A stillbirth or baby born with cleft lip and/or palate, neural tube defect and congenital cardiac abnormalities5 
      • If maternal fasting homocysteine is high following investigations of foetal death associated with foetal  growth restriction, pre-eclampsia, maternal thrombosis and/or maternal family history of thrombosis5
      • Stroke with elevated homocysteine

DNA testing may reveal that a person has either one or two MTHFR variants.  There are currently no recommended changes in clinical management based on an MTHFR test result.

Some people that are homozygous for the MTHFR C677T variant may develop a mild to moderate increased blood homocysteine level or hyperhomocysteinaemia.  This alone does not usually cause any symptoms or health problems, however further testing may be considered, such as B12, red blood cell folate and homocysteine.

Table 2 - Potential MTHFR variant test results
Remember some results will be completely normal - i.e. no variant found 


NTDs are multifactorial conditions.  Being homozygous for the C677T variant (TT) has been associated with low red blood cell folate and has been identified as a risk factor for neural tube defects3. Folic acid supplementation, prior to, and during, early pregnancy, has been shown to increase folate status to that which is considered protective for neural tube defects, regardless of the mother's MTHFR status2.

It is recommended that all women, regardless of their MTHFR genetic testing result, folic acid supplements (0.5mg per day) be taken for at least 1 month prior to possible conception and continued at that level for the first 3 months of pregnancy.

Women who have had a previous child with a neural tube defect, have a family history of neural tube defect, or are C677T homozygotes may require a higher dose of folic acid when planning a pregnancy.


MTHFR Patient Guide - click to download/print pdf



1. WHO. (2015). Guideline: Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects. In. (Geneva, World Health Organisation.

2. Crider, K.S., Zhu, J.-H., Hao, L., Yang, Q.-H., Yang, T.P., Gindler, J., Maneval, D.R., Quinlivan, E.P., Li, Z., Bailey, L.B., et al. (2011). MTHFR 677C→T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. The American Journal of Clinical Nutrition 93, 1365-1372.

3. Botto, L.D., and Yang, Q. (2000). 5, 10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review. American Journal of Epidemiology 151, 862-877.

4. Yang, Q., Bailey, L., Clarke, R., Flanders, W.D., Liu, T., Yesupriya, A., Khoury, M.J., and Friedman, J.M. (2012). Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults. The American Journal of Clinical Nutrition 95, 1245-1253.

5. Perinatal Society of Australia and New Zealand. (2009). Perinatal Mortality Audit Guideline. In. (

6. Burgunder, J.M., Finsterer, J., Szolnoki, Z., Fontaine, B., Baets, J., Van Broeckhoven, C., Di Donato, S., De Jonghe, P., Lynch, T., Mariotti, C., et al. (2010). EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias. European Journal of Neurology 17, 641-648.

7. Regland, B., Forsmark, S., Halaouate, L., Matousek, M., Peilot, B., Zachrisson, O., and Gottfries, C.-G. (2015). Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis and Fibromyalgia. PLoS ONE 10, e0124648.


Last updated: Nov 05, 2015