ClinVar Miner

Submissions for variant NC_012920.1(MT-TL1):m.3260A>G

dbSNP: rs199474663
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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 RCV004595477 SCV005088556 likely pathogenic Mitochondrial disease 2023-05-22 reviewed by expert panel curation The m.3260A>G variant in MT-TL1 has been reported in five unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 1677065, 8210299, 8941275, 20965148, 24656211). Three individuals had features variably consistent with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; PMIDs: 8941275, 20965148, 24656211) and two individuals had cardiomyopathy and skeletal muscle myopathy (PMIDs: 1677065, 8210299). There are no reported de novo occurrences to our knowledge. This variant segregated with disease in one of the reported families, as five affected family members had heteroplasmy levels ranging from 86% - 90% whereas unaffected family members had heteroplasmy levels ranging from 20% - 78% (PP1_moderate; PMID: 1677065). 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 (81st percentile) and HmtVAR predicts it to be pathogenic score of 0.7 (PP3). Studies in cybrids and yeast support the functional impact of this variant (PS3_supporting; PMIDs: 8132749, 19631764). 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 May 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3, PS3_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000850698 SCV000992930 pathogenic MELAS syndrome 2019-07-12 criteria provided, single submitter clinical testing The NC_012920.1:m.3260A>G variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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, PS5, PM7
OMIM RCV004554596 SCV000030443 pathogenic MITOCHONDRIAL CARDIOMYOPATHY WITH OR WITHOUT SKELETAL MYOPATHY 1994-03-01 no assertion criteria provided literature only
GeneReviews RCV000850698 SCV004042646 not provided MELAS syndrome no assertion provided literature only

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