ClinVar

Description

The m.3271T>C variant in MT-TL1 gene has been reported in more than 40 affected individuals from 20 kindreds (PS4; PMIDs: 1932147, 8482977, 7993661, 8908402, 9766710, 9427220, 11404119, 11828557, 10214753, 12609508, 16006433, 15794182, 16353243, 18206799, 20972245, 25680467, 33951347). The age of onset ranged from early childhood to the late 30s. This variant has been seen in individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS; accounts for approximately 10% of cases of MELAS and is the second most common cause) as well as in one individual with myoclonic epilepsy with ragged red fibers (MERRF). Other features seen in affected individual include muscle weakness, exercise intolerance, fatigue, developmental delay, axonal neuropathy, dementia, migraines, seizures, diabetes, growth hormone deficiency, lipoma, sensorineural hearing loss, hypertrophic cardiomyopathy, Wolff-Parkinson-White arrhythmia, optic atrophy, and short stature. Muscle biopsies showed ragged red fibers, COX-negative fibers, paracrystalline inclusions, hypertrophic/atrophic fibers, enlarged mitochondria, abnormal cristae, increased fat droplets, and variable respiratory chain enzyme activities. Heteroplasmy levels were variable but were highest in muscle and urine, and levels were as high as homoplasmic in muscle. This variant segregated with disease in multiple affected members across several families and several healthy family members had lower levels of the variant (PP1_moderate; PMIDs: 9427220, 16006433, 15794182, 18206799, 25680467). There is one report of a de novo occurrence, however technology at the time could have missed low level variants and the tissue(s) tested was not specified (PMID: 11828557). 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 (78.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Cybrid studies and other assays supported the functional impact of this variant (PS3_moderate; PMIDs: 12527767, 12729737, 15870203, 16120315, 10660592, 9744809, 7603512, 8280119). In summary, this variant meets criteria to be classified as 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 April 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_moderate.