Homocystinuria due to methylene tetrahydrofolate reductase deficiency: genes and variants

Genes linked to Homocystinuria due to methylene tetrahydrofolate reductase deficiency

• MTHFR: Methylenetetrahydrofolate reductase (NADPH)

  It generates 5-methyltetrahydrofolate for remethylation of homocysteine to methionine, linking folate metabolism with methyl-group supply. Severe biallelic deficiency causes homocystinuria with neurologic and thrombotic complications, while common variants produce much smaller effects on homocysteine.

  43 disease-causing and 148 uncertain variants in MTHFR are linked to Homocystinuria due to methylene tetrahydrofolate reductase deficiency.

Known disease-causing variants in Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Uncertain variants in Homocystinuria due to methylene tetrahydrofolate reductase deficiency that look disease-causing

Which prediction tools work for Homocystinuria due to methylene tetrahydrofolate reductase deficiency

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 84 out of 100
• SIFT: 84 out of 100
• phyloP: 75 out of 100

Same protein, different disease

• Neural tube defects, folate-sensitive is also caused by MTHFR variants; they fall mostly in different places as the Homocystinuria due to methylene tetrahydrofolate reductase deficiency variants (19 disease-causing).

Diseases related to Homocystinuria due to methylene tetrahydrofolate reductase deficiency

• Neural tube defects, folate-sensitive, also linked to MTHFR
• Thrombophilia due to thrombin defect, also linked to MTHFR
• Schizophrenia, also linked to MTHFR

Frequently asked questions

Which genes are linked to Homocystinuria due to methylene tetrahydrofolate reductase deficiency?

In CATVariant, Homocystinuria due to methylene tetrahydrofolate reductase deficiency is linked to 1 analyzed protein: MTHFR (Methylenetetrahydrofolate reductase (NADPH)).

How many genetic variants are linked to Homocystinuria due to methylene tetrahydrofolate reductase deficiency?

233 variants: 43 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 148 are of uncertain significance or have conflicting reports.

Which uncertain variants in Homocystinuria due to methylene tetrahydrofolate reductase deficiency look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example MTHFR R157W. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Homocystinuria due to methylene tetrahydrofolate reductase deficiency?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.84, based on 31 disease-causing and 13 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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