Creation of an Expert Curated Variant List for Clinical Genomic Test Development and Validation: A ClinGen and GeT-RM...

Area of Science:

• Genomic medicine
• Clinical diagnostics
• Bioinformatics

Background:

• Genomic sequencing tests analyze numerous genes, requiring robust validation.
• Identifying and procuring comprehensive reference materials for test validation is a significant challenge for clinical laboratories.
• Expert knowledge for variant identification and the availability of characterized genomic DNA reference materials are often insufficient.

Purpose of the Study:

• To address the challenge of validating genomic sequencing tests.
• To develop a publicly accessible list of expert-curated, clinically significant genetic variants.
• To provide a foundational resource for clinical genomic test development and validation.

Main Methods:

• Collaboration between the Centers for Disease Control and Prevention's Genetic Testing Reference Material Program (GeT-RM) and the Clinical Genome Resource (ClinGen).
• Nomination of variants by ClinGen Variant Curation Expert Panels.
• Inclusion of common pathogenic and difficult-to-detect variants across 84 disease-associated genes.

Main Results:

• A curated list of 546 variants was developed.
• Variants included single nucleotide variants, deletions, copy number variants, duplications, deletion-insertions, inversions, insertions, complex rearrangements, difficult-to-sequence regions, and fusions.
• The list covers 84 disease-associated genes.

Conclusions:

• The expert-curated variant list serves as a crucial resource for laboratories.
• This resource facilitates the design of comprehensive validation studies for clinical genomic tests.
• It supports the creation of in silico reference materials for test development and quality assurance.