Pathogenicity assessment of genetic variants in reproductive disorders.

PURPOSE: This review aims to summarize the available methods and current challenges in assessing the pathogenicity of genetic variants associated with reproductive disorders, with a particular focus on variants affecting oocyte maturation and early embryonic development. It also discusses how functional studied, computational approaches, and clinical evidence can be integrated with the ACMG/AMP framework to support more accurate variant interpretation and clinical decision-making. METHODS: In this review, we included the ACMG/AMP guidelines, studies on genes related to oocyte maturation and early embryonic development, and research on ACMG/AMP-based pathogenicity assessment tools. We searched PubMed, Embase, and Web of Science for literature published up from January 2000 to June 2026. We excluded pre-2000 publications (except foundational articles) and non-English papers. Results were reported descriptively. RESULTS: The application of the ACMG/AMP general framework to variants associated with oocyte maturation defects and early embryonic arrest faces challenges. In infertility-related variant interpretation, there are clinical practice barriers, difficulties in obtaining functional evidence, limitations of general population databases, and high false-positive rates of in silico prediction tools that collectively result in pathogenic variants being classified as variants of uncertain significance (VUS). Corresponding adaptation strategies include prioritizing reproduction-specific databases (IMIGC, FeRGI), introducing gene-/domain-specific weighting, employing automated ACMG-based classification tools (Franklin, VarSome, InterVar) with manual review, and adopting organoid technology for high-level functional evidence. CONCLUSION: Accurate interpretation of genetic variants associated with reproductive disorder requires integrating clinical evidence, functional study together with ACMG/AMP general framework. Gene-specific standards, supported by reproductive databases and calibrated evidence rules, may improve molecular diagnosis and personalized assisted reproductive technology (ART) strategy. A ClinGen Variant Curation Expert Panel (VCEP) focusing on oocyte and embryonic developmental deficiencies may also be required.