Performance of a Protein Language Model for Variant Annotation in Cardiac Disease

• Published in: Journal of the American Heart Association 2024-10, Vol.13 (20), p.e036921
• Main Authors: Hochstadt, Aviram, Barbhaiya, Chirag, Aizer, Anthony, Bernstein, Scott, Cerrone, Marina, Garber, Leonid, Holmes, Douglas, Knotts, Robert J, Kushnir, Alex, Martin, Jacob, Park, David, Spinelli, Michael, Yang, Felix, Chinitz, Larry A, Jankelson, Lior
• Format: Article
• Language: English
• Subjects: AlphaMissense; artificial intelligence; genetic testing; genotype; phenotype; VarCard.Io
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.124.036921

Genetic testing is a cornerstone in the assessment of many cardiac diseases. However, variants are frequently classified as variants of unknown significance, limiting the utility of testing. Recently, the DeepMind group (Google) developed AlphaMissense, a unique artificial intelligence-based model, based on language model principles, for the prediction of missense variant pathogenicity. We aimed to report on the performance of AlphaMissense, accessed by VarCardio, an open web-based variant annotation engine, in a real-world cardiovascular genetics center. All genetic variants from an inherited arrhythmia program were examined using AlphaMissense via VarCard.io and compared with the ClinVar variant classification system, as well as another variant classification platform (Franklin by Genoox). The mutation reclassification rate and genotype-phenotype concordance were examined for all variants in the study. We included 266 patients with heritable cardiac diseases, harboring 339 missense variants. Of those, 230 (67.8%) were classified by ClinVar as either variants of unknown significance or nonclassified. Using VarCard.io, 198 variants of unknown significance (86.1%, 95% CI, 80.9-90.3) were reclassified to either likely pathogenic or likely benign. The reclassification rate was significantly higher for VarCard.io than for Franklin (86.1% versus 34.8%,