ArticleNature genetics2024
Saturation genome editing maps the functional spectrum of pathogenic VHL alleles.
Article in Nature genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed.
- AlphaGenome Atlas:medRxiv : the preprint server for health sciences · 2026Article
- Minigene-based characterization and classification of splice-associated variants in succinate dehydrogenase B.NPJ precision oncology · 2026Article
- Reclassification ofCurrent oncology (Toronto, Ont.) · 2026Article
- Deciphering protein mutation-phenotype linkages from CRISPR-based tiling mutagenesis screens.Cell systems · 2026Article
- Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).Cancer metastasis reviews · 2026Review
- Multiplatform curation in the development of ACMG/AMP specifications for Von Hippel-Lindau (VHL) disease.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Surface electrostatic networks control hydrophobic core remodeling in a pH-dependent switching protein.bioRxiv : the preprint server for biology · 2026Article
- 'Truthsets' for clinical validation of large-scale functional assays: Practice recommendations from Cancer Variant Interpretation Group UK (CanVIG-UK).medRxiv : the preprint server for health sciences · 2026Article
- Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy.Circulation · 2026Article
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- Von Hippel-Lindau Syndrome: An Updated Narrative Review for the First-Contact Clinician.Cureus · 2026Review
- Comprehensive resistance profiling of chronic myeloid leukaemia associated ABL1 variants against five tyrosine kinase inhibitors using prime editing.Nature biomedical engineering · 2026Article
- Gene regulatory networks: from correlative models to causal explanations.Nature reviews. Genetics · 2026Review
- Causal Prediction of TP53 Variant Pathogenicity Using a Perturbation-Informed Protein Language Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- A multiplex, prime editing framework for identifying drug resistance variants at scale.Cell genomics · 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
- Saturation Genome Editing TargetingCurrent issues in molecular biology · 2026Article
- Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.Nature reviews. Cardiology · 2026Review
- Review
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
To maximize the impact of precision medicine approaches, it is critical to identify genetic variants underlying disease and to accurately quantify their functional effects. A gene exemplifying the challenge of variant interpretation is the von Hippel-Lindautumor suppressor (VHL). VHL encodes an E3 ubiquitin ligase that regulates the cellular response to hypoxia. Germline pathogenic variants in VHL predispose patients to tumors including clear cell renal cell carcinoma (ccRCC) and pheochromocytoma, and somatic VHL mutations are frequently observed in sporadic renal cancer. Here we optimize and apply saturation genome editing to assay nearly all possible single-nucleotide variants (SNVs) across VHL's coding sequence. To delineate mechanisms, we quantify mRNA dosage effects and compare functional effects in isogenic cell lines. Function scores for 2,268 VHL SNVs identify a core set of pathogenic alleles driving ccRCC with perfect accuracy, inform differential risk across tumor types and reveal new mechanisms by which variants impact function. These results have immediate utility for classifying VHL variants encountered clinically and illustrate how precise functional measurements can resolve pleiotropic and dosage-dependent genotype-phenotype relationships across complete genes.
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