Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods

Area of Science:

• Genetics
• Clinical Genetics
• Bioinformatics

Background:

• The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines face challenges in interpreting variants for specific genes like MECP2, CDKL5, FOXG1, UBE3A, SLC9A6, and TCF4.
• These genes are associated with complex neurodevelopmental disorders, necessitating refined interpretation strategies.

Purpose of the Study:

• To evaluate the clarity and accuracy of gene-specific modifications to ACMG/AMP variant interpretation criteria developed by the Rett and Angelman-like Disorders Variant Curation Expert Panel (Rett/AS VCEP).
• To assess the impact of these customized criteria on variant classification consistency and clinical relevance.

Main Methods:

• A pilot study involving multiple curators was conducted to apply the Rett/AS VCEP's gene-specific variant interpretation criteria.
• Curators independently interpreted 87 variants in the specified genes using the modified guidelines.
• Results were compared to original classifications and ClinVar entries.

Main Results:

• Approximately 90% of variants (78 out of 87) achieved consistent interpretation among curators using the modified guidelines.
• The classification of 13 variants changed compared to previous curations, influenced by internal data and updated criteria strength.
• No two-step classification changes occurred, and only one clinically significant change (Likely pathogenic to Variant of Unknown Significance) was observed.

Conclusions:

• The gene-specific variant curation rules developed by the Rett/AS VCEP demonstrate high inter-curator reliability and accuracy.
• These customized criteria enhance the interpretation of variants in MECP2, CDKL5, FOXG1, UBE3A, SLC9A6, and TCF4, aiding clinical decision-making.
• The Rett/AS VCEP's approach offers a valuable framework for interpreting variants in other fully penetrant, early-onset genes associated with rare disorders.