ClinVar Genomic variation as it relates to human health

The m.7510T>C variant in MT-TS1 has been reported in at least nine individuals across six different families with primary mitochondrial disease (PS4_moderate; PMIDs: 29299381, 18028453, 23430555, 15292920, 10978361, 12471220). The most common feature in affected individuals was sensorineural hearing loss. Age of onset ranged from 2-70 years old, and heteroplasmy levels in affected individuals ranged from 90% to >99%. Of note, some unaffected family members had the variant present at homoplasmy, as well (PMID: 12471220). Additional clinical features were seen in at least two families. One family reported in the medical literature also had migraines, ataxia, short stature, epilepsy, cognitive impairment, tremor, and restless leg syndrome (PMID: 29299381). The second family was known to some members of this expert panel, and the expert panel agreed to include this case. This variant segregated with disease manifestations in two families with hearing loss as all affected individuals had the variant present at heteroplasmy levels ranging from 90% to >99% (PP1_moderate; PMIDs: 29299381, 10978361). There are no de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3). There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3.