ClinVar Miner

Submissions for variant NC_012920.1(MT-TL1):m.3251A>G

dbSNP: rs199474662
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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 RCV004791201 SCV005407788 likely pathogenic Mitochondrial disease 2024-04-22 reviewed by expert panel curation The m.3251A>G variant in MT-TL1 has been reported in four unrelated individuals with primary mitochondrial disease to date. Age of onset ranged from the first decade of life to adulthood and clinical features in affected individuals were variably consistent with chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and early death. Heteroplasmy ranged from 13-95% in affected individuals (PS4_moderate; PMIDs: 8265770, 38465286, 8786060, 30837005). This variant segregated with clinical manifestations in one family with CPEO, progressive muscle weakness, and early death. The variant was present in the proband at 81% in muscle and 13% in blood and was present in maternal cousins at heteroplasmy levels of 25-16% (PP1; PMID: 8265770). There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 43.5%; HmtVAR: 0.75). Single fiber testing showed higher levels of the variant in COX-negative fibers (61%, range 15-88%) than in COX-positive fibers (28%, range 3%-86%; p<0.001; PS3_supporting, PMID: 8786060). There is additional evidence showing deleterious effects of this variant on the tRNA (PMID: 33380464). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the compelling functional validation and consistent phenotype observed in reported cases. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PM2_supporting, PS3_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000850691 SCV000992923 pathogenic MELAS syndrome 2019-07-12 criteria provided, single submitter clinical testing The NC_012920.1:m.3251A>G 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, PM8, PM9, PP4, PP6
Mendelics RCV000850691 SCV002517707 pathogenic MELAS syndrome 2022-05-04 criteria provided, single submitter clinical testing
OMIM RCV000010218 SCV000030442 pathogenic Progressive external ophthalmoplegia, proximal myopathy, and sudden death 1996-03-01 no assertion criteria provided literature only

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