ClinVar

Description

The m.5690A>G variant in MT-TN has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). One individual was a male with features consistent with Kearns Sayre syndrome including ptosis, ophthalmoplegia, cardiac conduction defects, myopathy, and ragged red fibers (PMID: 23847141, additional clinical details obtained from correspondence with author team). This individual had the variant present at 47% in muscle and no mitochondrial DNA single large scale deletions were identified. The second individual was a female with chronic progressive external ophthalmoplegia (CPEO) and myopathy (PMID: 23696415). The variant was present at 35% in muscle and was undetectable in her urine and blood. Testing in family members was not reported or not assessed for these two individuals, therefore it is unclear if the variant arose de novo or was present at lower levels in healthy family members. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (75.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). Single fiber testing showed higher levels of the variant in COX-deficient fibers (86.8 ± 18.3%) than in COX-positive fibers (27.9 ± 31.3%, p<0.0001, PMID: 23696415; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given similar features were seen in the two reported individuals with this variant and the strong single fiber study that was performed. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PS3_supporting.