The m.10663T>C (p.V65A) variant in MT-ND4L has been reported in at least 28 individuals from eight families, all of whom had Leber Hereditary Optic Neuropathy (LHON) and were haplogroup J and L (PS4_moderate; PMIDs: 29210930, 11935318, 24568867, 22879922, 17003408). There are three reported cases with no family history and, while these variants were assumed to occur de novo, family members were not tested for the variant. Several extended families have been reported in the medical literature (PMID: 24568867) however the variant was homoplasmic and thus prevented consideration for PP1. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are several occurrences in population databases, however some of these are from reported affected individuals (two occurrences in the GenBank dataset however one is from a patient with known mitochondrial disease, one occurrence in the Helix dataset, absent in gnomAD). Although there are several occurrences, the frequency is still low (PM2_supporting). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 11935318). This variant meets criteria to be classified as uncertain significance however this Expert Panel elected to modify the classification to likely pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common variants associated with LHON. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PS4_moderate, PM2_supporting, PP3.