Autosomal dominant optic atrophy (ADOA) is an important cause of irreversible visual impairment in children and adolescents. About 60–90% of ADOA is caused by the pathogenic variants of OPA1 gene. By evaluating the pathogenicity of OPA1 variants and summarizing the relationship between the genotype and phenotype, this study aimed to provide a reference for clinical genetic test involving OPA1. Variants in OPA1 were selected from the exome sequencing results in 7092 cases of hereditary eye diseases and control groups from our in-house data. At the same time, the urine cells of some optic atrophy patients with OPA1 variants as well as their family members were collected and oxygen consumption rates (OCR) were measured in these cells to evaluate the pathogenicity of variants. As a result, 97 variants were detected, including 94 rare variants and 3 polymorphisms. And the 94 rare variants were classified into three groups: pathogenic (33), variants of uncertain significance (19), and likely benign (42). Our results indicated that the frameshift variants at the 3′ terminus might be pathogenic, while the variants in exon 7 and intron 4 might be benign. The penetrance of the missense variants was higher than that of truncation variants. The OCR of cells with pathogenic OPA1 variants were significantly lower than those without pathogenic variants. In conclusion, some variants might be benign although predicted pathogenic in previous studies while some might have unknown pathogenesis. Measuring the OCR in urine cells could be used as a method to evaluate the pathogenicity of some OPA1 variants.

常染色体显性遗传性视神经萎缩（ADOA）是儿童和青少年不可逆视力障碍的重要原因。约60–90％的ADOA是由OPA1基因的致病变异引起的。通过评估OPA1变异的致病性并总结基因型与表型之间的关系，本研究旨在为涉及OPA1的临床遗传学检测提供参考。根据我们的内部数据，从7092例遗传性眼病和对照组的外显子组测序结果中选择了OPA1的变体。同时，一些视神经萎缩的OPA1患者的尿细胞收集变种及其家族成员，并在这些细胞中测量耗氧率（OCR），以评估变种的致病性。结果，检测到97个变体，包括94个稀有变体和3个多态性。94个罕见变体分为三类：致病性（33），意义不确定的变体（19）和可能是良性的（42）。我们的结果表明，在3'末端的移码变异可能是致病的，而外显子7和内含子4的变异可能是良性的。错义变体的外在性比截短变体的外在性高。致病性OPA1细胞的OCR变异明显低于没有致病变异的变异。总之，尽管在先前的研究中预测有致病性，但某些变体可能是良性的，而某些变体的发病机制尚不清楚。测量尿细胞中的OCR可以用作评估某些OPA1变体的致病性的方法。