Variant: NC_012920.1:m.12316G>A

CA913170089

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 11910924-ad21-49b7-8de6-d7dc0aa50165

HGVS expressions

NC_012920.1:m.12316G>A
J01415.2:m.12316G>A

Uncertain Significance

• Met criteria codes: PS4_Supporting PS3_Supporting PP3 PM2_Supporting

• Not Met criteria codes: BP4 PS2 PP1 PM6

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.12316G>A variant in MT-TL2 has been reported in three unrelated individuals with primary mitochondrial disease. The three individuals had chronic progressive external ophthalmoplegia (CPEO). Other features seen included peripheral neuropathy, myopathy, and exercise intolerance. Muscle biopsy in affected individuals revealed ragged red fibers, COX-negative fibers, and decreased activities of respiratory chain complexes I and IV. The levels of the variant in affected individuals ranged from 40-55.6% in muscle when reported. Levels in other tissues varied from undetectable to 10% (PS4_supporting; PMIDs: 23847141, 20163808, 18603265). There are no large families reported in the medical literature to consider for evidence of segregation. There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (83.7 percentile) as does HmtVar with a score of 0.6 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed a higher degree of heteroplasmy in ragged red fibers (87.4% ± 8.5, n = 4) and COX-deficient fibers (59.7% ± 27.8, n = 4) compared to COX-positive muscle fibers (wild type mtDNA only, n = 6, Fig. 2). The difference between COX-positive and ragged red fibers was statistically significant (p<0.00001; PMID: 20163808; 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 February 27, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PS3_supporting.

Met criteria codes

• PS4_Supporting: The m.12316G>A variant in MT-TL2 has been reported in three unrelated individuals with primary mitochondrial disease. The three individuals had chronic progressive external ophthalmoplegia (CPEO). Other features seen included peripheral neuropathy, myopathy, and exercise intolerance. Muscle biopsy in affected individuals revealed ragged red fibers, COX-negative fibers, and decreased activities of respiratory chain complexes I and IV. The levels of the variant in affected individuals ranged from 40-55.6% in muscle when reported. Levels in other tissues varied from undetectable to 10% (PS4_supporting; PMIDs: 23847141, 20163808, 18603265).
• PS3_Supporting: Single fiber testing showed a higher degree of heteroplasmy in ragged red fibers (87.4% ± 8.5, n = 4) and COX-deficient fibers (59.7% ± 27.8, n = 4) compared to COX-positive muscle fibers (wild type mtDNA only, n = 6, Fig. 2). The difference between COX-positive and RRF fibres was statistically significant (p<0.00001; PMID: 20163808; PS3_supporting).
• PP3: The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (83.7 percentile) as does HmtVar with a score of 0.6 (PP3).
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).

Not Met criteria codes

• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: There are no reported de novo occurrences of this variant to our knowledge.
• PP1: There are no large families reported in the medical literature to consider for evidence of segregation.
• PM6: There are no reported de novo occurrences of this variant to our knowledge.

Approved on: 2023-02-27

Published on: 2023-03-15