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.
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© 2021 Published by Elsevier Inc.