ClinVar

Description

The m.14484T>C (p.M64V) variant in MT-ND6 has been reported in >50 unrelated individuals with primary mitochondrial disease (PS4). This variant is one of the three most common variants associated with Leber Hereditary Optic Neuropathy (LHON; PMID: 20301353) and is associated with a less severe phenotype, with visual recovery seen in some individuals. The age of onset ranges from adolescence to adulthood. While most affected individuals with this variant have LHON, other features have been seen including migraines (PMID: 12601121), tremor (PMID: 8931573), multiple sclerosis (PMIDs: 10098545, 35773337), and cardiac involvement (PMIDs: 12807863, 22749828). This variant is consistently seen in the homoplasmic state (PMIDs: 9484365, 24508359, 28392196, PMID: 9339703, 8659531, 7611298, 7604366, 7603534, 8071952, 7877803, 1463007, 1417830, 1732158, 2018041). Several extended families have been reported in the medical literature however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for segregation evidence of pathogenicity. There is at least one de novo occurrence reported in the medical literature (PM6_supporting; PMID: 9339703). Furthermore, the presence of this variant in individuals from different haplogroups suggests this variant occurred de novo in the ancestors of these individuals of different backgrounds. This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Other variants at this amino acid position leading to a different amino acid change are known disease-associated variants – m.14482C>G and m.14482C>A that both result in p.M64I (PM5). Multiple independent studies support the functional impact of this variant (PS3_moderate). Eleven cybrid studies revealed various effects including decreased ND6, ND1, and ND4L levels; decreased complex I activity; respiratory deficiency; diminished mitochondrial ATP production; reduced membrane potential; and increased production of reactive oxygen species (ROS). Cybrid cells also had increased apoptosis, autophagy, and mitophagy (PMIDs: 35567411, 25909222, 20943885, 19047048, 18806273, 15883259, 15342361, 12446713, 12379308, 35858578). In summary, this variant meets criteria to be classified as pathogenic 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 September 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP3, PM5, PM6_supporting, PS3_moderate.