MTHFR C677T variant

The C677T polymorphism (rs1801133) in methylenetetrahydrofolate reductase (MTHFR) encodes a thermolabile enzyme with reduced activity (approximately 70–75% reduction in TT homozygotes — retaining only ~25–30% residual activity — and ~35% reduction in CT heterozygotes, particularly under low-folate conditions) and causes modest elevation of plasma homocysteine. Elevated homocysteine has been epidemiologically associated with cardiovascular disease and neural tube defects, and the variant is correspondingly associated with those outcomes, though the causal role of homocysteine itself remains debated. The clinical relevance of MTHFR C677T genotyping is contested: major laboratory and genetics societies advise against routine population testing, noting that the association is modest, diet-modifiable, and that homocysteine-lowering B-vitamin supplementation has not consistently reduced cardiovascular events in trials. Despite its limited clinical actionability, it remains one of the most over-ordered genetic tests in functional medicine contexts.