APOE ε4 variant interpretation and protein numbering discrepancy: a case report.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia worldwide, and the apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset form. Differences in protein numbering conventions may complicate recognition of clinically important variants during genomic interpretation. METHODS: We report a 57-year-old man with early-onset AD who underwent next-generation sequencing (NGS). Genetic findings were interpreted using transcript, protein, and dbSNP annotations to assess the clinical significance of the identified variant. RESULTS: NGS identified a homozygous APOE variant annotated as p.Cys130Arg. This annotation corresponds to the APOE ε4-defining rs429358 variant, commonly reported as Cys112Arg in the mature protein sequence. The variant was initially classified as a variant of uncertain significance (VUS) in the clinical genetic report. Subsequent review demonstrated that p.Cys130Arg and Cys112Arg represent equivalent annotations of the same rs429358 allele. CONCLUSIONS: This case highlights how alternative protein numbering conventions may complicate variant interpretation and underscores the importance of integrating genomic, transcript, protein, and dbSNP-level information during clinical genomic analysis.