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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 age1 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. MTHFR acts in association with a number of other genes as a threshold risk factor, and is not usually individually significant.
  4. Folic acid supplementation has been shown to increase folate levels, regardless of MTHFR status,  to that which is considered protective for neural tube defects2.
  5. MTHFR variants are unlikely to have any impact on health in the absence of low red blood cell folate or high homocysteine.  
  6. 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.

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).


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


There is insufficient evidence 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:

MTHFR testing attracts a Medicare rebate only if there is a proved DVT/PE or a known mutation in a first degree relative.

MTHFR testing as part of an investigation for  infertility or as a direct-to-consumer test currently occurs in some organisations in NSW.

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 fetal death associated with fetal  growth restriction, pre-eclampsia, maternal thrombosis and/or maternal family history of thrombosis5

Stroke with elevated homocysteine6 


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 a 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, take folic acid supplements (0.5mg per day) for at least 1 month prior to possible conception and continue to take 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 GENE TESTING FOR PATIENTS - click to download Fact Sheet 64


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. 

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: Aug 18, 2016