ClinGen Glaucoma Variant Curation Expert Panel recommendations enhance classification of myocilin variants.

Pathogenic MYOC variants are the most common Mendelian cause of open-angle glaucoma, with every pathogenic or likely pathogenic variant lying within the conserved olfactomedin domain encoded by exon 3.

The ClinGen Glaucoma Variant Curation Expert Panel applied its updated rule specifications to 271 MYOC variants reported in people with open-angle glaucoma, following a 2022 pilot study of 81 variants. Curation yielded 11 benign, 45 likely benign, 166 uncertain, 35 likely pathogenic and 14 pathogenic variants, with all likely pathogenic and pathogenic variants located in the olfactomedin domain encoded by exon 3. Clinically definitive classifications rose from 28% (74/265) to 39% (105/271), and 95% (41/43) of reclassified variants moved toward greater clinical relevance. Functional evidence was missing for 93% (154/166) of the variants of uncertain significance. The authors estimate that additional functional data could halve that category (85/166).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Rule recalibration buys about ten percentage points of usable classifications, yet 61% of MYOC variants remain unresolved and the further gain the authors project rests entirely on functional data that do not exist yet. In clinic the immediate benefit is limited to the variants actually reclassified; for the rest, reporting should stay cautious and ophthalmological follow-up be driven by the family phenotype. This is a medRxiv preprint, so it is worth waiting for the peer-reviewed version before carrying these classifications into a clinical report.

Analysis by Dr Thibaut Benquey