ClinVar Miner

Submissions for variant NC_012920.1:m.3291T>C

dbSNP: rs869312463
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen RCV002291215 SCV002583524 likely pathogenic Mitochondrial disease 2022-10-03 reviewed by expert panel curation The m.3291T>C variant in MT-TL1 has been reported in at least eight unrelated individuals with primary mitochondrial disease. Ages of onset varied from 6- to 40-years old. Affected individuals had variable features including those consistent with MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) as well as myopathy, sensorineural hearing loss, and cognitive decline. Muscle biopsies in affected individuals showed ragged red fibers (RRF), whereas respiratory chain enzyme deficiencies were variable. Heteroplasmy levels ranged from 20-95% (PS4_moderate; PMIDs: 7520241, 10899447, 18977334, 20943236, 21996807, 21863273, 23273904). There are at least two de novo occurrences of this variant reported (PM6_moderate; PMIDs: 20943236, 7520241). Heteroplasmy levels tracked with disease manifestations in at least three families (PP1_moderate; PMIDs: 23273904, 21863273, 10899447). 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 and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18) than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904). 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 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM6_moderate, PP1_moderate, PM2_supporting, PP3, PS3_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000850711 SCV000992944 pathogenic Juvenile myopathy, encephalopathy, lactic acidosis AND stroke 2019-07-12 criteria provided, single submitter clinical testing The NC_012920.1:m.3291T>C variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5
Mendelics RCV000850711 SCV002517712 pathogenic Juvenile myopathy, encephalopathy, lactic acidosis AND stroke 2022-05-04 criteria provided, single submitter clinical testing
GeneReviews RCV000850711 SCV004042644 not provided Juvenile myopathy, encephalopathy, lactic acidosis AND stroke no assertion provided literature only

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