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Pathogenic <jats:italic>EARS2<\/jats:italic> variants cause combined oxidative phosphorylation deficiency, subtype 12 (COXPD12), an autosomal recessive disorder involving lactic acidosis, intellectual disability, and other features of mitochondrial compromise. Patients with EARS2 deficiency present with variable phenotypes ranging from neonatal lethality to a mitigated disease with clinical improvement in early childhood. Here, we report a neonate homozygous for a rare pathogenic variant in <jats:italic>EARS2<\/jats:italic> (c.949G&gt;T; p.G317C). Metabolomics in primary fibroblasts from this patient revealed expected abnormalities in TCA cycle metabolites, as well as numerous changes in purine, pyrimidine, and fatty acid metabolism. To examine genotype\u2010phenotype correlations in COXPD12, we compared the metabolic impact of reconstituting these fibroblasts with wild\u2010type <jats:italic>EARS2<\/jats:italic> versus four additional <jats:italic>EARS2<\/jats:italic> variants from COXPD12 patients with varying clinical severity. Metabolomics identified a group of signature metabolites, mostly from the TCA cycle and amino acid metabolism, that discriminate between <jats:italic>EARS2<\/jats:italic> variants causing relatively mild and severe COXPD12. Taken together, these findings indicate that metabolomics in patient\u2010derived fibroblasts may help establish genotype\u2010phenotype correlations in <jats:italic>EARS2<\/jats:italic> deficiency and likely other mitochondrial disorders.<\/jats:p>","DOI":"10.1002\/jimd.12387","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T16:48:23Z","timestamp":1618505303000},"page":"949-960","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Metabolic impact of pathogenic variants in the mitochondrial <scp>glutamyl\u2010tRNA<\/scp> synthetase <scp>EARS2<\/scp>"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4587-1622","authenticated-orcid":false,"given":"Min","family":"Ni","sequence":"first","affiliation":[{"name":"Children's Medical Center Research Institute The University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Department of 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The University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Department of Biochemistry The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bookyung","family":"Ko","sequence":"additional","affiliation":[{"name":"Children's Medical Center Research Institute The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Cai","sequence":"additional","affiliation":[{"name":"Children's Medical Center Research Institute The University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Quantitative Biomedical Research Center The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Solmonson","sequence":"additional","affiliation":[{"name":"Children's Medical Center Research Institute The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chendong","family":"Yang","sequence":"additional","affiliation":[{"name":"Children's Medical Center Research Institute The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly M.","family":"Nugent","sequence":"additional","affiliation":[{"name":"Children's Hospital of San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick V.","family":"Grishin","sequence":"additional","affiliation":[{"name":"Department of Biophysics The University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Department of Biochemistry The University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Howard Hughes Medical Institute The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Xing","sequence":"additional","affiliation":[{"name":"Eugene McDermott Center for Human Growth and Development The University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Department of Bioinformatics The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Roeder","sequence":"additional","affiliation":[{"name":"Children's Hospital of San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph J.","family":"DeBerardinis","sequence":"additional","affiliation":[{"name":"Children's Medical Center Research Institute The University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Department of Pediatrics The University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Howard Hughes Medical Institute The University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Eugene McDermott Center for Human Growth and Development The University of Texas Southwestern Medical Center  Dallas Texas 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