Study of the impact of ClinGen Revisions on ACMG/AMP variant semi-automatic classification for Rare Diseases diagnosis

Abstract

With the rapid development of massive sequencing technologies, the analysis of genetic variants for clinical diagnosis has exponentially escalated, particularly in the context of Rare Diseases (RDs). Diagnosing them involves identifying the genetic variants responsible for the underlying pathology development. In 2015, the American College of Medical Genetics (ACMG) established a set of recommendations to assess the evidence associated with each variant, aiming to achieve a standardized five tier classification. Over the past 5 years, ClinGen, the NIH-funded Clinical Genome Resource, has reviewed these criteria in order to make variant classification a more reproducible and rigorous process. This paper examines the impact of ClinGen-Rev modifications on variant classification, comparing them with the ACMG-2015 original recommendations. After analyzing sets of genetic variants, extracted from VCFs samples, using both criteria, we observed a change in 8.0 % of the clinical verdicts for these variants. ClinGen-Rev modifications correctly categorized 89.2 % of the curated variants, representing a significant improvement compared to the 65.6 % achieved by ACMG-2015. We also analyzed the modifications impact in a real like clinical setting, showing a significant overall reduction of VUS variants and thus potential reduction in analysis time. Finally, we discuss the underlying reasons for the most relevant changes in terms of specific labels and present their implications on the prioritization and selection process of variants, identifying some recommendations of key significant importance.