Last updated 3mo ago
A 28-year-old woman with a history of recurrent first-trimester pregnancy losses is found to be homozygous for the MTHFR c.677C>T (p.Ala222Val) variant on a "thrombophilia panel" ordered by her OB/GYN. She is referred to genetics to discuss the implications. She has no personal or family history of thrombosis.
MTHFR (methylenetetrahydrofolate reductase), 1p36.22
- Encodes enzyme that converts 5,10-methylenetetrahydrofolate → 5-methyltetrahydrofolate (active folate)
- Active folate is needed for homocysteine → methionine conversion
- Two common variants:
- c.677C>T (p.Ala222Val): Thermolabile enzyme with ~30% reduced activity (heterozygous) or ~65% reduced activity (homozygous). Homozygosity frequency: ~10-15% in many populations.
- c.1298A>C (p.Glu429Ala): Mildly reduced enzyme activity. Less clinically significant.
- Compound heterozygosity (677CT/1298AC) can mildly elevate homocysteine
What MTHFR variants DO:
- Homozygous c.677C>T can cause mild-to-moderate hyperhomocysteinemia, particularly with low folate intake
- Mildly increased neural tube defect risk in homozygous mothers (addressed by standard folic acid supplementation)
- Homocysteine levels normalize with adequate folate
What MTHFR variants DO NOT do (common misconceptions):
- Not a significant independent risk factor for venous thromboembolism; ACMG does not recommend testing
- Not a cause of recurrent pregnancy loss per ACOG
- Not an indication for anticoagulation
- Should not be included on thrombophilia panels (ACMG position statement)
- Not a cause of "methylation disorders" as promoted by some alternative medicine practitioners
Key concept: MTHFR common variants (especially c.677C>T homozygosity) are frequently encountered but rarely clinically actionable. The main role for genetic counselors is managing patient expectations and countering misinformation.
- MTHFR genotyping is widely available but not recommended by ACMG, ACOG, or AHA as part of routine thrombophilia or recurrent pregnancy loss evaluation
- If tested and found homozygous c.677C>T: check homocysteine level
- Elevated homocysteine is the clinically relevant finding, not the genotype itself
- Homocysteine elevation has many causes (B12 deficiency, folate deficiency, renal disease, hypothyroidism)
- Standard folic acid supplementation (400-800 mcg/day for all women of childbearing age) is sufficient
- If homocysteine is elevated: folate, B6, and B12 supplementation to normalize levels
- No indication for aspirin, anticoagulation, or special "methylated folate" supplements based solely on genotype
- Genetic counseling focuses on education, reassurance, and addressing misinformation
- Refer to ACMG practice guideline on MTHFR testing
MTHFR = "Mostly Trivial, Hyped, Folate-Responsive": Homozygous c.677C>T causes mild enzyme reduction that is corrected by folate. It is not a thrombophilia and should not be on clotting panels.