MTHFR is the gene that codes for the enzyme methylenetetrahydrofolate reductase. This enzyme converts folate into its active form (5-methyltetrahydrofolate), which is needed to turn homocysteine back into the amino acid methionine.
The best-known variant of this gene is the C677T polymorphism. It makes the enzyme thermolabile and less active. In carriers of two copies of the variant (the 677TT genotype) folate is activated less well, and the blood homocysteine level may be slightly elevated.
What the MTHFR enzyme does
MTHFR sits at the centre of the folate cycle. It converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate — precisely the form of folate that donates a methyl group for the "remethylation" of homocysteine into methionine (this reaction also needs vitamin B12). Methionine then forms SAM, the universal donor of methyl marks, which takes part among other things in DNA methylation.
The C677T and A1298C polymorphisms
The two best-studied variants are C677T (the 677C>T substitution, leading to the amino-acid change Ala222Val) and A1298C. The C677T variant makes the enzyme thermolabile: at normal body temperature its activity is reduced. The homozygous 677TT genotype occurs in about 10–15% of people of European descent and more often (up to ~25%) in some Latin American populations. In such carriers the homocysteine level is on average slightly higher, especially against a background of low folate intake.
What it means in practice
For most C677T carriers this is only a predisposition to moderate hyperhomocysteinemia, not a disease. Far more important is the body's actual supply of folate and B12: with sufficient intake of folate (or its active form, methylfolate) and vitamin B12, homocysteine usually stays normal. Severe forms (homocystinuria) are caused by other, rare mutations of the gene, not by the common polymorphism. Mass testing for MTHFR without indications is generally not recommended.
Calculate using this marker
Calculators where MTHFR (gene and polymorphism) is used directly:
Frequently asked questions
Does everyone need an MTHFR test?
As a rule, no. It is more informative to assess the actual homocysteine level and the supply of folate and B12. The MTHFR genotype by itself rarely changes management in a healthy person.
Is the C677T polymorphism dangerous?
By itself — usually not. In most carriers it causes only a mild rise in homocysteine, which is corrected by adequate intake of folate and vitamin B12.