Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical...

Area of Science:

• Genomics
• Clinical Genetics
• Bioinformatics

Background:

• Genomic variant interpretation, especially for copy number variants (CNVs), faces challenges in resolving discrepancies.
• Dosage sensitivity, including haploinsufficiency (HI) and triplosensitivity (TS), is crucial for classifying pathogenic variants.
• Standardized interpretation of CNVs involving dosage-sensitive genes is essential for consistent patient care.

Purpose of the Study:

• To assess the accuracy of clinical CNV interpretations in ClinVar by comparing them against the ClinGen Dosage Map.
• To identify and re-evaluate CNVs overlapping known dosage-sensitive genes that were not classified as likely pathogenic (LP) or pathogenic (P).
• To improve the quality and consistency of genomic variant data in public databases.

Main Methods:

• Comparison of germline CNV interpretations in ClinVar with the ClinGen Dosage Map, which documents HI and TS genes/regions.
• Identification of CNVs overlapping dosage-sensitive genes but lacking LP/P classification.
• Re-evaluation of identified CNVs by their original submitting laboratories.

Main Results:

• 251 CNVs overlapping known dosage-sensitive genes were identified without LP/P classification.
• Following re-evaluation of 246 CNVs, 157 (63.8%) received updated clinical classifications.
• No changes were made to 79 (32.1%) classifications, and 10 (4.1%) resulted in other record updates.

Conclusions:

• The study highlights significant discrepancies in CNV interpretation, necessitating re-evaluation against established dosage sensitivity data.
• Re-evaluation led to a substantial number of updated classifications, enhancing the reliability of genomic variant data.
• This process contributes curated data to the public domain, aiding laboratories in focusing on complex interpretation challenges.