ClinVar

Description

The m.5650G>A variant in MT-TA has been reported in three unrelated individuals with primary mitochondrial disease. The predominant feature in these individuals was myopathy (muscle weakness, exercise intolerance), and other features were seen in one individual each (lipomas, ptosis, migraines, sensorineural hearing loss, impaired glucose tolerance). Age of onset varied from teens to young adulthood and all individuals were alive at the time of report. Brain imaging was variable in the three individuals and muscle biopsies showed ragged red fibers, COX-negative fibers, and respiratory chain enzyme deficiencies. Lab values were significant for variably elevated lactate and CK. There was a range of variant heteroplasmy levels in tissues from each individual although the heteroplasmy level was consistently highest in muscle (PS4_supporting, PMIDs: 14569122, 17825557, 11715067). Of note, one individual also had a NOTCH3 pathogenic variant (PMID: 11715067), however this expert panel elected to include this case given NOTCH3 pathogenic variants are associated with CADASIL (cerebral arteriopathy with subcortical infarcts and leukoencephalopathy), and this individual had additional features that were consistent with a primary mitochondrial disease. This variant segregated with disease in two families: one family with an unaffected sister having the variant present at lower heteroplasmy levels than the proband (PMID: 14569122) and one family with an affected mother with similarly high levels of the variant to the proband and a less severely affected maternal grandmother with lower heteroplasmy levels (PMID: 17825557; PP1_supporting). There are no reports of de novo occurrences to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (77th percentile) and HmtVAR predicts it to be pathogenic score of 0.9 (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 three reported individuals. In one individual, the variant was essentially present at homoplasmy in ragged red fibers (n=11) and at 62% in normal fibers (n=11, p<0.01; PMID: 14569122). In the other individual, the variant was present at 99.0 ± 0.29% (n = 9) in COX-deficient fibers compared to 87.6 ± 2.26% (n = 15) in COX-positive fibers (p<0.0008, PMID: 17825557). Additionally, there is a mouse model of this variant with features consistent with primary mitochondrial disease (PMID: 27626666) that shows improvement when heteroplasmy is shifted (PMIDs: 30250142, 34050192). The combination of strong single fiber testing and mouse model led this expert panel to increase the weight of this criterion to moderate (PS3_moderate). 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 October 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_supporting, PM2_supporting, PP3, PS3_moderate.