3. Standardizing recurrent copy number variant classification – From benign to reduced and high penetrance regions

Recurrent copy number variants (CNVs), particularly those with low penetrance, are a common source of variant classification and reporting practice discrepancies. In order to assist clinical laboratories in the interpretation of these events, the ClinGen Dosage Sensitivity working group is developing a curation metric that mirrors existing ClinGen curation methods and the recently published ACMG/ClinGen CNV classification guidelines. This metric incorporates clinical reports from the peer-reviewed literature, gene-level dosage sensitivity, phenotypic specificity/variability, segregation and inheritance patterns, and case-control data, to objectively evaluate and appropriately weight information across different evidence categories. More recently, we have also incorporated a review of additional CNV classification evidence categories for up/down-grading the potential pathogenicity of CNVs, including protein-coding gene counts and general population frequencies from DGV gnomAD. Starting with the “Dosage Sensitivity Unlikely” curation category, which corresponds to a “Likely-Benign”/“Benign” classification, we have refined classification for variants present at a high frequency in the general population (>0.1% or >1%), for which no consistent phenotypic association has been made and which are commonly inherited from unaffected parents. While further defining this category, we recently updated scores and reviews for several regions including duplications of the 2p13 (NPHP1), 13q12.12, 15q11.2 (BP1-BP2), 15q13.3 (D-CHRNA7 to BP5), 16p12.2 (distal, OTOA), and Xp22.31 (STS) regions. Defining regions that are unlikely to be dosage sensitive through evidence-based review provides significant value to the clinical CNV interpretation process, and paves the way for inclusion of additional non-LCR/SD-mediated CNV regions in future work by our committee. This work adds to an ongoing effort by our group to curate approximately 50 recurrent CNV regions using the new points-based metric, with which we have already scored 26 regions. Overall, this work aims to provide better consistency to recurrent CNV classification, interpretation, and reporting in the clinical setting, particularly for CNVs with reduced penetrance.