ClinVar Genomic variation as it relates to human health

The m.3258T>C variant in MT-TL1 has been reported in at least three probands to date. The first case report was a young adult with severe hyperlactatemia associated with mild exercise intolerance and mild lipidosis. This individual had a combined respiratory chain deficiency in liver with normal activities in muscle. This proband’s mother died in early adulthood from an unexplained cause The variant was listed as being heteroplasmic but the levels were not reported (PMID: 11335700). The second case was a young adult with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) characterized by fatigue, acidosis, hyperCKemia, stroke-like episodes, and tonic clonic seizures; with ragged red fibers and COX negative fibers on muscle biopsy. The variant was present at 96% in muscle and 57% in blood (PMID: 12798797). The third case was younger at presentation with neurological involvement (ataxia, regression, myoclonic epilepsy) as well as decreased complex I and IV activities in muscle, increased lactate in blood and CSF, and a normal brain MRI. Heteroplasmy levels were not provided (PMID: 23847141). Haplogroup information was not reported for all cases however given the features and biochemistry reported in these cases, this Expert Panel agreed to consider them as a supporting line of evidence (PS4_supporting). The variant segregated with features of primary mitochondrial disease and unaffected status in three family members from one family. The variant was present at 96% in muscle and 57% in blood in the proband whereas in her healthy mother had the variant at 19% in blood, one healthy brother had the variant at 30% in blood, and another healthy brother had the variant at 48% in blood (PP1; PMID:12798797). There is one occurrence of this variant in GenBank dataset, however this is from an individual with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 82.6%, as does HmtVar with a score of 0.8 (PP3). Single fiber analysis in muscle showed that the ragged red fiber had extremely high levels of variant (n = 7; 99.4% +/- 0.9%), whereas normal muscle fibers had significantly lower levels (n = 8; 90.1 +/- 5.1%; P < 0:05, Mann–Whitney’s U-test) (PS3_supporting, PMID: 12798797). 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 the evidence shown in single fibers studies for this variant and because the phenotype reported in these cases is consistent with mitochondrial tRNA-related diseases. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PM2_supporting, PP1, PP3, PS4_supporting, PS3_supporting.

The MT-TL1 m.3258T>C mitochondrial variant results in the substitution of thymidine at mitochondrial nucleotide position m.3258 with cytosine. This variant has been previously identified in three individuals with a phenotype consistent with primary mitochondrial disease (PMID: 11335700; PMID:12798797; PMID:23847141). A single-fiber study conducted using patient muscle tissue demonstrated a correlation between mitochondrial respiration and variant heteroplasmy (PMID: 12798797). This variant has been shown to segregate with disease in an affected family, with lower heteroplasmy levels associated with unaffected status (PMID: 12798797). This variant is not observed at a significant frequency in version 3.1.2 of the Genome Aggregation Database or in MITOMAP. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the m.3258T>C variant is classified as likely pathogenic for primary mitochondrial disease.