ArticleAmerican journal of human genetics2023
The functional impact of 1,570 individual amino acid substitutions in human OTC.
Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 22 citations in OpenAlex.
- Interpreting human genetic variation at atomic resolution.Nature genetics · 2026Review
- Functional profiling of 2,193 ASS1 missense variants: Insights into variant pathogenicity and epistatic interactions in citrullinemia type I.PLoS genetics · 2026Article
- Determining the intra-residue correlation of missense variant impact using MAVE scores: implications for the ACMG/AMP PM5 criterion for DNA variant classification.Genome medicine · 2026Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- Predicting epistasis across proteins by structural logic.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- MaveMD: A functional data resource for genomic medicine.medRxiv : the preprint server for health sciences · 2025Article
- acmgscaler: an R package and Colab for standardized gene-level variant effect score calibration within the ACMG/AMP framework.Bioinformatics (Oxford, England) · 2025Article
- Biochemical Characterization of Disease-Associated Variants of Human Ornithine Transcarbamylase.ACS chemical biology · 2025Article
- Gene-based calibration of high-throughput functional assays for clinical variant classification.bioRxiv : the preprint server for biology · 2025Article
- Rare biochemical & genetic conditions: clues for broader mechanistic insights.Cellular and molecular life sciences : CMLS · 2025Review
- Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes.Nature communications · 2025Article
- Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection.American journal of human genetics · 2024Article
- Use of pure recombinant human enzymes to assess the disease-causing potential of missense mutations in urea cycle disorders, applied to N-acetylglutamate synthase deficiency.Journal of inherited metabolic disease · 2024Article
- Article
- High-throughput assays to assess variant effects on disease.Disease models & mechanisms · 2024Article
- Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database.Molecular genetics & genomic medicine · 2024Review
- ProteinGym: Large-Scale Benchmarks for Protein Design and Fitness Prediction.bioRxiv : the preprint server for biology · 2023Article
- Constructing and interpreting a large-scale variant effect map for an ultrarare disease gene: Comprehensive prediction of the functional impact of PSAT1 genotypes.PLoS genetics · 2023Article
- Diagnostic and Management Issues in Patients with Late-Onset Ornithine Transcarbamylase Deficiency.Children (Basel, Switzerland) · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Deleterious mutations in the X-linked gene encoding ornithine transcarbamylase (OTC) cause the most common urea cycle disorder, OTC deficiency. This rare but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. Individuals with neonatal onset appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death, outcomes ameliorated by rapid diagnosis and treatment. Here, we develop a high-throughput functional assay for human OTC and individually measure the impact of 1,570 variants, 84% of all SNV-accessible missense mutations. Comparison to existing clinical significance calls, demonstrated that our assay distinguishes known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation. This functional stratification allowed us to identify score ranges corresponding to clinically relevant levels of impairment of OTC activity. Examining the results of our assay in the context of protein structure further allowed us to identify a 13 amino acid domain, the SMG loop, whose function appears to be required in human cells but not in yeast. Finally, inclusion of our data as PS3 evidence under the current ACMG guidelines, in a pilot reclassification of 34 variants with complete loss of activity, would change the classification of 22 from variants of unknown significance to clinically actionable likely pathogenic variants. These results illustrate how large-scale functional assays are especially powerful when applied to rare genetic diseases.
Indexed as
Identifiers
What OpenQuestion holds
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.