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Updated: Jun 18, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
"Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders"
Sarah Martin1, Tina Jenewein2,3, Christof Geisen3
1Centre for Sudden Cardiac Death and Familial Arrhythmias, Institute of Legal Medicine, University Hospital Frankfurt, Goethe-University, Frankfurt/Main, Germany. sarah.martin2136@gmail.com.
Background:
Genetic diagnostics support the diagnosis of hereditary arrhythmogenic diseases, but variants of uncertain significance (VUS) complicate matters, emphasising the need for regular reassessment. Our study aims to reanalyse rare variants in different genes in order to decrease VUS diagnoses and thus improve risk stratification and personalized treatment for patients with arrhythmogenic disorders.
Methods:
Genomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts.
Results:
We identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017-2019, with rates ranging from 50 to 60%.
Conclusion:
The results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach.
