Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert...

Area of Science:

• Genetics
• Genomic Medicine
• Molecular Biology

Background:

• The ClinGen RASopathy (RAS) Variant Curation Expert Panel (VCEP) developed initial specifications for the American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) variant classification framework.
• Evolving understanding of RASopathies and new genetic testing algorithms necessitated an update to these specifications for improved accuracy.

Purpose of the Study:

• To update RASopathy variant classification specifications for the ACMG/AMP framework based on advancements in RASopathy knowledge and genetic testing.
• To enhance the consistency and accuracy of variant classification in RASopathies.

Main Methods:

• The RAS Gene Curation Expert Panel re-evaluated six gene-disease relationships and previous specifications.
• Updated RASopathy specifications were developed for the ACMG/AMP framework.
• The performance of the updated specifications was validated by reassessing 59 previously classified variants and 88 new pilot variants.

Main Results:

• Five gene-disease relationships were upgraded to 'Definitive' and one to 'Moderate' classification.
• Updated specifications were applied to 11 dominant and 3 recessive inheritance criteria, plus 4 criteria aligned with the ClinGen Sequence Variant Interpretation Working Group.
• Variant re-assessment showed no significant discrepancies compared to prior RAS VCEP or ClinVar classifications.

Conclusions:

• The updated RASopathy specifications notably improve variant classification for recessive diseases and cases analyzed via exome/genome sequencing.
• These refined specifications can serve as a foundational framework for classifying variants in other rare Mendelian disorders.