ArticleAmerican journal of human genetics2021
Shifting landscapes of human MTHFR missense-variant effects.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
48 citing papers in PubMed, 79 citations in OpenAlex.
- Interpreting human genetic variation at atomic resolution.Nature genetics · 2026Review
- Systematic and proactive evaluation of AIRE missense variant effects.American journal of human genetics · 2026Article
- Why variant effect predictors and multiplexed assays agree and disagree.Nature communications · 2026Article
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant-effect predictors.HGG advances · 2026Article
- Integrated multi-omics analysis reveals folate metabolism-related genes as prognostic markers and therapeutic targets in clear cell renal cell carcinoma.BMC cancer · 2026Article
- Article
- 5,10-Methylenetetrahydrofolate Reductase─the Key Allosteric Regulator in One-Carbon Metabolism.Biochemistry · 2026Review
- Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.Nature reviews. Cardiology · 2026Review
- CodonMutator: a python-based automated oligonucleotide design framework for deep mutational scanning library construction.BMB reports · 2026Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- Rosace-AA: enhancing interpretation of deep mutational scanning data with amino acid substitution and position-specific insights.Bioinformatics advances · 2026Article
- MTHFR and ABCB1 polymorphisms associated with toxicity in hematological malignancies patients receiving high dose methotrexate.Scientific reports · 2025Article
- Systematic and proactive evaluation of AIRE missense variant effects.bioRxiv : the preprint server for biology · 2025Article
- acmgscaler: an R package and Colab for standardized gene-level variant effect score calibration within the ACMG/AMP framework.Bioinformatics (Oxford, England) · 2025Article
- Landscapes of missense variant impact for human superoxide dismutase 1.American journal of human genetics · 2025Article
- Variant scoring tools for deep mutational scanning.Molecular systems biology · 2025Review
- Homocysteine in the Cardiovascular Setting: What to Know, What to Do, and What Not to Do.Journal of cardiovascular development and disease · 2025Review
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- Cosmos: A Position-Resolution Causal Model for Direct and Indirect Effects in Protein Functions.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
21 authors at 8 institutions in 4 countries.
Funding
Abstract
Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.