ReviewAmerican journal of human genetics2021
Opportunities and challenges for the computational interpretation of rare variation in clinically important genes.
Review 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 50 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
50 citing papers in PubMed, 91 citations in OpenAlex.
- Use of Next-Generation Sequencing and Whole-Exome Sequencing in the Diagnosis of Adult-Onset Familial Intrahepatic Cholestasis: Challenges in Interpreting Variants of Uncertain Significance.Diagnostics (Basel, Switzerland) · 2026Review
- Precision Grounding: augmenting large language models with evidence-based databases for trustworthy genetic variant summarization.International journal of medical informatics · 2026Article
- Multi-Level Genomic and Computational Analyses Identify a Novel IFT122 Variant Associated With Cranioectodermal Dysplasia 1 in a Consanguineous Saudi Family.Molecular genetics & genomic medicine · 2026Article
- Integrating the Genomic Revolution into Newborn Screening: Current Challenges and Future Perspectives.Pediatric reports · 2026Review
- Functional Validation of a Novel Deep IntronicThe application of clinical genetics · 2026Article
- Health technology design considerations specific to Indigenous Data Sovereignty and implementation science.Frontiers in health services · 2026Article
- Beyond the Exome: The Role of Noncoding and Regulatory Variants in Monogenic Diseases.Current issues in molecular biology · 2025Review
- Accelerated Identification and Preliminary Validation of a Pathogenic Missense Variant in the L1CAM Gene in a Pregnant Woman With Sonographic Anomalies Using AlphaMissense.Molecular genetics & genomic medicine · 2025Article
- In utero precision medicine for severe, early-onset neurogenetic disease: scientific, clinical and ethical considerations.Pediatric research · 2025Article
- Special Issue "Ion Conductance and Ion Regulation in Human Health and Disease".International journal of molecular sciences · 2025Article
- Increasing pathogenic germline variant diagnosis rates in precision medicine: current best practices and future opportunities.Human genomics · 2025Review
- Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational tools.Molecular genetics and metabolism reports · 2025Article
- Evolution, genetic diversity, and health.Nature medicine · 2025Review
- Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing.Genetics in medicine open · 2025Article
- Genes to therapy: a comprehensive literature review of whole-exome sequencing in neurology and neurosurgery.European journal of medical research · 2024Review
- Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- VUS next in rare diseases? Deciphering genetic determinants of biomolecular condensation.Orphanet journal of rare diseases · 2024Review
- The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients.Journal of human genetics · 2024Article
- Review
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 6 institutions in 1 country.
Funding
Abstract
Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.
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.