ClinVar

Description

The m.12276G>A variant in MT-TL2 has been reported in four unrelated individuals with primary mitochondrial disease. Chronic progressive external ophthalmoplegia and myopathy were seen in three cases (PMIDs: 15649400, 15591266, 23847141), and two of these cases had pigmentary retinopathy (PMIDs: 15649400, 23847141). The fourth case had a progressive encephalopathy (PMID: 20022607). Muscle biopsies in affected individuals showed ragged red fibers, COX-negative fibers, and normal to reduced respiratory chain enzyme activities. Heteroplasmy levels were consistently highest in muscle, ranging from 18-81%, and were low (6-8%) to undetectable in other tissues (PS4_moderate, PMIDs: 15649400, 15591266, 23847141, 20022607). The variant was confirmed to have occurred de novo in one of the reported individuals (variant absent in blood and urine of healthy mother and sister, PMID: 20022607; PM6_supporting). There are no large families reported in the medical literature with testing performed to consider for evidence of segregation. The computational predictor MitoTIP suggests this variant is pathogenic (74.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). This variant is absent in the Helix dataset and gnomAD v3.1.2, and the single occurrence in the GenBank dataset is from an affected individual (PM2_supporting). Single fiber testing was performed in two of the four reported cases (PS3_supporting). In one case, fibers with <75% of the variant exhibited normal COX/SDH ratios and fibers with 80% or higher had severe deficiency of COX activity (PMID: 15591266). In another individual (PMID: 20022607), COX-deficient fibers had ~80% heteroplasmy and COX-positive fibers had ~25% heteroplasmy, a statistically significant difference (p<0.001). 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PP3, PS3_supporting.