ArticleAmerican journal of human genetics2018
Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity.
Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 91 citations in OpenAlex.
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- When splicing is not all or none: GT>GC 5' splice-site variants as a model for intermediate effects and challenges in variant classification.HGG advances · 2026Article
- Base editing and nanoparticle transfection of airway cell types essential for treatment of cystic fibrosis.JCI insight · 2026Article
- Base editing and nanoparticle transfection of airway cell types essential for treatment of cystic fibrosis.bioRxiv : the preprint server for biology · 2025Article
- Higher Throughput Assays for Understanding the Pathogenicity of Variants of Unknown Significance in the RPE65 Gene.Investigative ophthalmology & visual science · 2025Article
- SPINK1-related chronic pancreatitis: A model that encapsulates the spectrum of variant effects, genetic complexity, and classificatory challenges.American journal of human genetics · 2025Article
- Diseases Common in Persons With Cystic Fibrosis Among CFTR Heterozygotes.JAMA internal medicine · 2025Article
- Higher throughput assays for understanding the pathogenicity of variants of unknown significance (VUS) in the RPE65 gene.bioRxiv : the preprint server for biology · 2025Article
- Influence of ADRB2 variants on bronchodilator response and asthma control in a mixed population.Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia · 2025Article
- The role of SLC26A8 homozygous variants in male infertility and flagellum abnormalities.Asian journal of andrology · 2024Article
- Scalable approaches for generating, validating and incorporating data from high-throughput functional assays to improve clinical variant classification.Human genetics · 2024Article
- GermlineProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Rare GPR37L1 Variants Reveal Potential Association between GPR37L1 and Disorders of Anxiety and Migraine.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Increased prevalence ofHeliyon · 2024Article
- Article
- Use of adenine base editing and homology-independent targeted integration strategies to correct the cystic fibrosis causing variant, W1282X.Human molecular genetics · 2023Article
- Protospacer modification improves base editing of a canonical splice site variant and recovery of CFTR function in human airway epithelial cells.Molecular therapy. Nucleic acids · 2023Article
- Genetic variant annotation scores in congenital long QT syndrome.Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2023Article
- Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype-phenotype relationship for variants reported to date.Lipids in health and disease · 2023Article
- Lynch syndrome, molecular mechanisms and variant classification.British journal of cancer · 2023Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
Missense DNA variants have variable effects upon protein function. Consequently, interpreting their pathogenicity is challenging, especially when they are associated with disease variability. To determine the degree to which functional assays inform interpretation, we analyzed 48 CFTR missense variants associated with variable expressivity of cystic fibrosis (CF). We assessed function in a native isogenic context by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR expression. 21 of 29 variants associated with full expressivity of the CF phenotype generated <10% wild-type CFTR (WT-CFTR) function, a conservative threshold for the development of life-limiting CF lung disease, and five variants had moderately decreased function (10% to ∼25% WT-CFTR). The remaining three variants in this group unexpectedly had >25% WT-CFTR function; two were higher than 75% WT-CFTR. As expected, 14 of 19 variants associated with partial expressivity of CF had >25% WT-CFTR function; however, four had minimal to no effect on CFTR function (>75% WT-CFTR). Thus, 6 of 48 (13%) missense variants believed to be disease causing did not alter CFTR function. Functional studies substantially refined pathogenicity assignment with expert annotation and criteria from the American College of Medical Genetics and Genomics and Association for Molecular Pathology. However, four algorithms (CADD, REVEL, SIFT, and PolyPhen-2) could not differentiate between variants that caused severe, moderate, or minimal reduction in function. In the setting of variable expressivity, these results indicate that functional assays are essential for accurate interpretation of missense variants and that current prediction tools should be used with caution.
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