Variant Curation and Classification in Rare Disease Genomics: Standards and Emerging Tools for Single-Nucleotide...

Area of Science:

• Clinical Genomics
• Rare Disease Diagnosis
• Bioinformatics

Background:

• Next-generation sequencing (NGS) has revolutionized rare disease diagnosis.
• Standardization of genetic variant analysis, classification, and interpretation is critical in clinical settings.

Purpose of the Study:

• To provide a practical overview of variant curation and classification frameworks for SNVs and small indels.
• To examine advances, achievements, limitations, and challenges in variant classification for rare disease diagnosis.

Main Methods:

• Review of current variant curation and classification frameworks.
• Examination of key developments including 2015 guidelines, population databases, computational predictors, and functional studies.
• Distinction between variant curation, classification, and clinical interpretation.

Main Results:

• Variant classification frameworks have advanced, improving molecular diagnosis.
• Achievements include refined guidelines, population databases, and predictive tools.
• Limitations persist, particularly with non-coding variants and database diversity.

Conclusions:

• Variant classification is essential for rare disease diagnosis, with ongoing progress and persistent challenges.
• Addressing interpretation of non-coding variants and updating classification frameworks are key future directions.
• Collaborative initiatives and improved predictors are needed to enhance diagnostic accuracy.