ClinVar Genomic variation as it relates to human health

The m.14482C>A (p.M64I) variant in MT-ND6 has been reported in at least five unrelated individuals with LHON (PS4_moderate; PMIDs: 19319978, 12112086, 11931086, 12150954). Ages of onset varied from 10-29-years-old. All affected individuals had the variant present at homoplasmy. There are no reports of de novo occurrences to our knowledge. Several extended families have been reported in the medical literature (PMIDs: 11931086, 12112086) however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for PP1. There are two occurrences of this variant in GenBank dataset, however both are from individuals with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). Another variant at this amino acid position leading to a different amino acid change is one of the most common causes of LHON and is a known pathogenic variant – m.14484T>C (p.M64V, PM5). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.96 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PM5, PP3.

This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status.