Toward streamline variant classification: discrepancies in variant nomenclature and syntax for ClinVar pathogenic variants across annotation tools
Journal
Human Genomics
Journal Volume
19
Journal Issue
1
Start Page
70
ISSN
1479-7364
Date Issued
2025-06-21
Author(s)
Chen, Yu-An
Yuan, Tzu-Hang
Huang, Jia-Hsin
Wang, Yu-Bin
Hung, Tzu-Mao
Abstract
Background: High-throughput sequencing has revolutionized genetic disorder diagnosis, but variant pathogenicity interpretation is still challenging. Even though the human genome variation society (HGVS) provides recommendations for variant nomenclature, discrepancies in annotation remain a significant hurdle. Results: In this study, we evaluated the annotation concordance between three tools—ANNOVAR, SnpEff, and variant effect predictor (VEP)—using 164,549 two-star variants from ClinVar. The analysis used HGVS nomenclature string-match comparisons to assess annotation consistency from each tool, corresponding coding impacts, and associated ACMG criteria inferred from the annotations. The analysis revealed variable concordance rates, with 58.52% agreement for HGVSc, 84.04% for HGVSp, and 85.58% for the coding impact. SnpEff showed the highest match for HGVSc (0.988), while VEP bettered for HGVSp (0.977). The substantial discrepancies were noted in the loss-of-function (LoF) category. Incorrect PVS1 interpretations affected the final pathogenicity and downgraded PLP variants (ANNOVAR 55.9%, SnpEff 66.5%, VEP 67.3%), risking false negatives of clinically relevant variants in reports. Conclusions: These findings highlight the critical challenges in accurately interpreting variant pathogenicity due to discrepancies in annotations. To enhance the reliability of genetic variant interpretation in clinical practice, standardizing transcript sets and systematically cross-validating results across multiple annotation tools is essential.
Subjects
ACMG guideline
ClinVar
HGVS nomenclature
Variant annotation
Variant interpretation
SDGs
Publisher
Springer Science and Business Media LLC
Type
journal article