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Interpretation of variants of uncertain significance is an actual major challenge. We addressed this question on a set of  OPA1  missense variants responsible for variable severity of neurological impairments. We used targeted metabolomics to explore the different signatures of  OPA1  variants expressed in  Opa1  deleted mouse embryonic fibroblasts ( Opa1  −/−  MEFs), grown under selective conditions. Multivariate analyses of data discriminated  Opa1 +/+   from  Opa1 −/−   MEFs metabolic signatures and classified  OPA1  variants according to their  in vitro  severity. Indeed, the mild p.I382M hypomorphic variant was segregating close to the wild-type allele, while the most severe p.R445H variant was close to  Opa1 −/−   MEFs, and the p.D603H and p.G439V alleles, responsible for isolated and syndromic presentations, respectively, were intermediary between the p.I382M and the p.R445H variants. The most discriminant metabolic features were hydroxyproline, the spermine/spermidine ratio, amino acid pool and several phospholipids, emphasizing proteostasis, endoplasmic reticulum (ER) stress and phospholipid remodeling as the main mechanisms ranking  OPA1  allele impacts on metabolism. These results demonstrate the high resolving power of metabolomics in hierarchizing  OPA1  missense mutations by their  in vitro  severity, fitting clinical expressivity. This suggests that our methodological approach can be used to discriminate the pathological significance of variants in genes responsible for other rare metabolic diseases and may be instrumental to select possible compounds eligible for supplementation treatment.

Metabolomics hallmarks OPA1 variants correlating with their in vitro phenotype and predicting clinical severity