The m.13084A>T (p.S250C) variant in MT-ND5 has been reported in one family with primary mitochondrial disease to date (PMIDs: 12509858, 33062892). The proband was a boy with features and brain imaging findings consistent with both Leigh syndromes spectrum disorder and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) including neurodegeneration, stroke-like episodes, seizures, myoclonic jerks, bradykinesia, ataxia, dysarthria, decreased visual acuity, ptosis, hearing loss, and right bundle branch block. Complex I activity was mildly reduced in muscle. The variant was present at 85% in muscle, 82% in blood, 99% in buccal cells, 67% in urine, and 72% in fibroblast cell line. The proband’s mother was more mildly affected with migraines and Leber Hereditary Optic Neuropathy (LHON). The variant was present at 75% in lymphocytes and 48% in fibroblasts. The proband’s sister had brisk reflexes and diffuse slow wave activity on electroencephalogram (EEG) and had the variant present at 41% in lymphocytes and 13% in fibroblasts (PP1). There are no additional individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.61 (Min=0, Max=1; APOGEE2 score is 0.883), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PP3, PM2_supporting.