The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • There was no gene found in the curated document received from the VCI/VCEP
  • The variant label for this record ("m.12320A>G") does not appear to be in HGVS format
  • No CSPEC computed assertion could be determined for this classification!


Variant: m.12320A>G

CA254838

9587 (ClinVar)

Gene: N/A
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
UUID: 25e4428e-5c4e-43fd-a332-4b94b2a6ff05
Approved on: 2024-04-22
Published on: 2024-11-20

HGVS expressions

NC_012920.1:m.12320A>G
J01415.2:m.12320A>G

Uncertain Significance

Met criteria codes 2
PS3_Supporting PM2_Supporting
Not Met criteria codes 5
PS2 PS4 PM6 PP1 PP3

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.12320A>G variant in MT-TL2 has been reported in one individual with primary mitochondrial disease to date (PMID: 9012410), in a woman with progressive myopathy, acidosis, ptosis, and ragged red and COX-negative fibers on muscle biopsy. The variant was present at 70% heteroplasmy in muscle on first biopsy and was found to be present at 90% on subsequent biopsy, coinciding with a 12-year progression in symptoms. There is no report of her family members being testing and there are no additional reports of large families with this variant segregating with disease. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 37.3%; HmtVAR: 0.7). Single fiber testing showed higher levels of the variant in COX-negative fibers (88-96%) compared to COX positive fibers (60-88%; PMID: 9450773; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance 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 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting.
Met criteria codes
PS3_Supporting
Single fiber testing showed higher levels of the variant in COX-negative fibers (88-96%) compared to COX positive fibers (60-88%; PMID: 9450773; PS3_supporting).

PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
Not Met criteria codes
PS2
There are no reported de novo occurrences of this variant to our knowledge.
PS4
The m.12320 A>G variant in MT-TL2 has been reported in one individual to date with primary mitochondrial disease. This individual had features of progressive myopathy, acidosis, ptosis, ragged red fibers and COX negative fibers. Heteroplasmy was 70% in muscle and increased to 90% over 12 year progression of symptoms. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals.
PM6
There are no reported de novo occurrences of this variant to our knowledge.
PP1
There are no reports of large families with this variant segregating with disease.
PP3
The computational predictor MitoTIP suggests this variant is benign (37.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.7.
Curation History
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