Clinical interpretation of DNA sequence variants is a crucial part of reporting results from genetic testing. The use of NGS has greatly advanced the diagnosis of genetic disorders in clinical settings. However, the vast number of DNA sequence variants identified in samples, including many that are novel, presents significant challenges for clinical interpretation.

This workshop will help develop and improve attendees’ skills and knowledge for interpreting genetic variants, including identification, classification, clinical relevance and utilizing relevant tools and resources.

Target Audience:

This workshop is primarily designed for clinical geneticists, genetic counselors, laboratory professionals and other healthcare providers involved in genetic testing and diagnostics. It would also be beneficial for bioinformaticians and researchers working in the field of genomics and precision medicine, especially those focused on interpreting genetic variants.

This workshop is designed to be interactive and engaging, allowing participants to gain hands-on experience with variant interpretation while discussing real-world applications and challenges.

Pre-Requisites:

This workshop targets users with a background in the fundamentals of variant analysis. If you don’t have this background or are unsure if you are ready for this workshop, you can do some background reading here:

Clinical Interpretation of Sequence Variants - PMC (nih.gov)

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology - PubMed (nih.gov)

Key Learnings:

• Understand available guidance for classifying variants based on provided evidence   

• Enhance interpretation using a software that offers comprehensive annotations and visualization of breakpoints and coverage across different file types in a full genome browser  
• Recognize current core tools and approaches to support genomic variant interpretation

Format and Agenda:

11.35  Variant Classification (20 min)

• Introduction to classification systems, focusing on the ACMG guidelines for variant interpretation
• Explanation of categories: benign, likely benign, uncertain significance, likely pathogenic, and pathogenic

Liz Worthey, Section Head, Director, and Associate Professor, UAB School of Medicine

11.50 Unlocking the Potential of Genetic Variants in Understanding Gene Function (15 min)

• Discuss how to leverage population-scale sequencing data of about a million individuals across diverse ancestries to understand rare variants and identify functionally important genes and regions
• Apply these insights and reference catalog of allele frequencies to refine the clinical assessment of pathogenic variants and variants of uncertain significance (VUS).
• Explore tools and resources derived from this data to make genetic variant analysis more accessible, aiding in accurate gene function prediction and variant impact assessment.

Suganthi Balasubramanian, Director, Computational Biology, Regeneron

12.10 Tools and Resources to Support Gene and Variant Interpretation (30 min)

• Overview of important resources such as ClinGen, ClinVar, gnomAD, GenCC, Federated Variant-Level Matching and others
• Demonstration of how to use these tools can assist in      gene      and variant interpretation      
• Understand future developments in professional standards for variant classification to reduce the VUS burden    

Heidi Rehm, Professor of Pathology, Massachusetts General Hospital and Broad Institute of MIT and Harvard    

12.40 Q&A and discussion and live demos time permitting (25 min)