ClinVar

Description

The m.14710G>A variant in MT-TE has been reported in two affected individuals from two families (PMIDs: 15670724, 23847141; PS4_supporting). These two individuals had similar courses, as both were women with onset in childhood or adolescence of progressive external ophthalmoplegia (PEO), myopathy, pigmentary retinopathy, and migraines. Muscle biopsies performed in these two individuals showed ragged red fibers and COX-negative fibers. Respiratory chain enzyme activities were normal except for reduced complex I activity in one individual. Heteroplasmy levels were only reported in one individual (PMID: 15670724), but were 67-77% in muscle, trace amounts to 14% in hair roots, and were undetectable in buccal, blood, and fibroblasts. Of note, exercise testing in one subject (PMID: 15670724) is described in other manuscripts (PMIDs: 11506394 and 12538407), and her case is also included in a cohort study (PMID: 19718780). One of the affected individuals has a son with autism but he was not tested for this variant. The variant was not detected in blood from the subject’s mother and three sisters but it was also undetectable in the subject's blood, so de novo status could not be confirmed (PMID: 15670724). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (93 ± 1.0%) than in COX positive fibers (59 ± 28%), p<0.005. Furthermore, COX-positive fibers showed a much greater range of mutated mtDNA than COX-negative fibers (9–89% vs 92–95%; PMID: 15670724; PS3_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (51.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that some experts on this panel voted for a classification of likely pathogenic given the evidence of pathogenicity (strong single fiber studies, absent in population databases and present in two individuals with similar features of primary mitochondrial disease). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 15, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PS3_supporting, PP3.