About this condition
MTHFR Gene Mutation
MTHFR encodes methylenetetrahydrofolate reductase, an enzyme critical for converting folate into its active form and regulating one-carbon metabolism — the pathway that converts the amino acid homocysteine into methionine. Two common polymorphisms exist: C677T, which reduces enzyme activity to roughly 30% of normal in homozygotes, and A1298C, which reduces activity to about 60%. In the rare severe form, biallelic pathogenic variants cause near-complete loss of enzyme function, leading to severe hyperhomocysteinemia and neurological complications.
Approximately 10% of North Americans are homozygous for the C677T polymorphism. Both polymorphisms are prevalent across populations with ethnogeographic variation. When folate status is low, carriers of these polymorphisms may develop mildly elevated homocysteine, which is associated with increased cardiovascular risk and, in women, modestly increased risk of neural tube defects in offspring. The rare severe form of MTHFR deficiency affects approximately 1 in 10,000 to 50,000 people globally and follows autosomal recessive inheritance.
Understanding MTHFR variants has immediate clinical implications. For individuals with elevated homocysteine, identifying a pathogenic MTHFR variant guides personalized folate and B-vitamin supplementation strategies. For carriers with the common C677T polymorphism, confirming the genotype informs family planning decisions and prenatal counseling. For severe deficiency, a genetic finding enables betaine therapy initiation, confirms the diagnosis, and guides cascade testing in family members — each sibling of an affected individual has a 25% recurrence risk.
MTHFR variants include both common polymorphisms (C677T and A1298C) and rare pathogenic variants causing severe deficiency — each with different enzymatic impact and clinical consequences.
- Gene locus
- MTHFR (1p36.22)
