Variant: m.12183G>A

CA120575

9609 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: f424889b-44a5-4540-829b-c8e5a20d42a7

Approved on: 2024-03-26

Published on: 2024-07-31

HGVS expressions

NC_012920.1:m.12183G>A
J01415.2:m.12183G>A

Uncertain Significance

• Met criteria codes: PS3_Supporting PP1_Moderate PM2_Supporting PP3

• Not Met criteria codes: PS2 PS4 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.12183G>A variant in MT-TH has been reported in one individual with primary mitochondrial disease to date, in a man with myopathy, ataxia, short stature, hypogonadism, retinopathy, cataracts, and sensorineural hearing loss (PMID: 12682337, also included in analysis in PMID: 19718780). The variant was present at 87.2% heteroplasmy in muscle and 38.3% in blood. This man’s sister had sensorineural hearing and pigmentary retinopathy, with the variant present at 21.2% in blood. Their mother with myopathy, cataracts, and hearing loss had the variant present at 12.4% in blood. The variant was undetectable in three healthy maternal aunts and one healthy maternal uncle (PP1_moderate; PMID: 12682337). There are no reported de novo occurrences to our knowledge. There is one occurrence in population databases (GenBank dataset, 1/61,134, an individual in haplogroup L3f; absent in gnomAD v3.1.2 and Helix dataset), however the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative and ragged red fibers (91.4% ± 4.9, n=7) than in COX-positive fibers (58.4% ± 12.8, n=7), p<0.005 (PS3_supporting, PMID: 12682337). The computational predictor MitoTIP suggests this variant is pathogenic (70.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). 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 March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PM2_supporting, PS3_supporting, PP3.

Met criteria codes

• PS3_Supporting: Single fiber testing showed higher levels of the variant in COX-negative and ragged red fibers (91.4% ± 4.9, n=7) than in COX-positive fibers (58.4% ± 12.8, n=7), p<0.005 (PS3_supporting, PMID: 12682337).
• PP1_Moderate: This man’s sister had sensorineural hearing and pigmentary retinopathy, with the variant present at 21.2% in blood. Their mother with myopathy, cataracts, and hearing loss had the variant present at 12.4% in blood. The variant was undetectable in three healthy maternal aunts and one healthy maternal uncle (PP1_moderate; PMID: 12682337).
• PM2_Supporting: There is one occurrence in population databases (GenBank dataset, 1/61,134, an individual in haplogroup L3f; absent in gnomAD v3.1.2 and Helix dataset), however the frequency is still low (PM2_supporting).
• PP3: The computational predictor MitoTIP suggests this variant is pathogenic (70.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3).

Not Met criteria codes

• PS2: There are no reported de novo occurrences to our knowledge.
• PS4: The m.12183G>A variant in MT-TH has been reported in one individual with primary mitochondrial disease to date, in a man with myopathy, ataxia, short stature, hypogonadism, retinopathy, cataracts, and sensorineural hearing loss (PMID: 12682337, also included in analysis in PMID: 19718780). The variant was present at 87.2% heteroplasmy in muscle and 38.3% in blood.
• PM6: There are no reported de novo occurrences to our knowledge.