ClinVar Miner

Submissions for variant NC_012920.1(MT-TS1):m.7497G>A

dbSNP: rs387906419
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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 RCV003319162 SCV004023279 likely pathogenic Mitochondrial disease 2023-04-17 reviewed by expert panel curation The m.7497G>A variant in MT-TS1 has been reported in three unrelated individuals with primary mitochondrial disease with shared features of exercise intolerance, proximal myopathy, lactic acidosis, and myalgia. Age at presentation ranged from three years old to the 30s. Muscle biopsies showed ragged red fibers, COX-negative fibers, and reduced activities of complexes I and IV. All probands were homoplasmic for the variant in muscle and it was present in various other tissues at levels >90%. (PS4_supporting; PMIDs: 14605505, 9778262). This variant segregated with disease in each of the three families reported (PP1_moderate). The probands were homoplasmic for the variant muscle and/or blood. In one family, the unaffected mother harbored the variant at 10% in blood (PMID: 14605505). In the second family, the unaffected mother harbored the variant at 62% and the unaffected brother had the variant at 62% in blood (PMID: 9778262). In the third family, an affected daughter with myalgia had the variant at 90% in blood and an unaffected brother has the variant at 70% (PMID: 9778262). There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (92.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activities (PS3_supporting, PMID: 16199753). 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 April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PS3_supporting, PM2_supporting, PP3.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000850901 SCV000993135 pathogenic MELAS syndrome 2019-07-12 criteria provided, single submitter clinical testing The NC_012920.1:m.7497G>A variant in MT-TS1 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
Mendelics RCV002247288 SCV002517726 pathogenic Mitochondrial complex IV deficiency, nuclear type 1 2022-05-04 criteria provided, single submitter clinical testing
OMIM RCV000010182 SCV000030405 pathogenic Exercise intolerance, muscle pain, and lactic acidemia 2003-01-01 no assertion criteria provided literature only

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