Complexity of genomic diagnosis: Lessons learnt from the UK Biobank and Generation study newborn genome sequencing analyses.

Reclassification of the COL1A2 p.(Gly943Arg) variant from pathogenic to VUS based on population frequency

A COL1A2 c.2827G>A p.(Gly943Arg) variant, a triple-helix glycine substitution classically deemed pathogenic, was identified through newborn genomic screening. After reassessment with gnomAD v4.1 (including the UK Biobank) and ACGS 2024 criteria, its population frequency proved inconsistent with osteogenesis imperfecta pathogenicity, prompting reclassification to VUS. The five carriers ranged from no fractures to moderately severe OI, with many asymptomatic adult heterozygotes and a shared haplotype enriched in Northwest England. No OI diagnoses were recorded among 44 adult heterozygotes in the UKBB.

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

A textbook case on the dynamics of variant classification in the genomic-screening era: a canonically pathogenic glycine substitution proves inconsistent with full penetrance. It underscores the power of large population datasets to recalibrate variants and the ethical challenges of reclassification after newborn screening. Caution is warranted toward pathogenicity rules based on variant type alone.

Analysis by Dr Thibaut Benquey