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In silico versus functional characterization of genetic variants: lessons from muscle channelopathies

Vivekanandam, Vinojini; Ellmers, Rebecca; Jayaseelan, Dipa; Houlden, Henry; Männikkö, Roope; Hanna, Michael G; (2022) In silico versus functional characterization of genetic variants: lessons from muscle channelopathies. Brain , 146 (4) pp. 1316-1321. 10.1093/brain/awac431. Green open access

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Abstract

Accurate determination of the pathogenicity of missense genetic variants of uncertain significance is a huge challenge for implementing genetic data in clinical practice. In silico predictive tools are used to score variants’ pathogenicity. However, their value in clinical settings is often unclear, as they have not usually been validated against robust functional assays. We compared nine widely used in silico predictive tools, including more recently developed tools (EVE and REVEL) with detailed cell-based electrophysiology, for 126 CLCN1 variants discovered in patients with the skeletal muscle channelopathy myotonia congenita. We found poor accuracy for most tools. The highest accuracy was obtained with MutationTaster (84.58%) and REVEL (82.54%). Both of these scores showed poor specificity, although specificity was better using EVE. Combining methods based on concordance improved performance overall but still lacked specificity. Our calculated statistics for the predictive tools were different to reported values for other genes in the literature, suggesting that the utility of the tools varies between genes. Overall, current predictive tools for this chloride channel are not reliable for clinical use, and tools with better specificity are urgently required. Improving the accuracy of predictive tools is a wider issue and a huge challenge for effective clinical implementation of genetic data.

Type: Article
Title: In silico versus functional characterization of genetic variants: lessons from muscle channelopathies
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awac431
Publisher version: https://doi.org/10.1093/brain/awac431
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: muscle channelopathies, genetic variants, variants of uncertain significance, myotonia
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10160318
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