Variant: NC_012920.1(MT-CYB):m.4308G>A

CA913177679

689875 (ClinVar)

Gene: MT-TI

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: c5b2f98b-a73a-4781-9bbc-85798e284191

Approved on: 2022-10-10

Published on: 2022-10-12

HGVS expressions

NC_012920.1:m.4308G>A
J01415.2:m.4308G>A

Uncertain Significance

• Met criteria codes: PM6_Supporting PP3 PS4_Supporting PM2_Supporting

• Not Met criteria codes: PS3 PP1

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.4308G>A variant in MT-TI has been reported in two unrelated individuals with primary mitochondrial disease with onset ranging from the first decade to third decade of life and features include bilateral ptosis, chronic progressive external ophthalmoplegia (CPEO), exercise intolerance, decreased BMI, and hyperCKemia. Muscle biopsy showed paracrystalline inclusions, ragged red fibers, COX negative fibers, and respiratory chain deficiencies across complexes I, III, and IV. In both cases, the variant was undetectable in blood when the individuals were tested in their 30s and 50s. The variant was heteroplasmic in muscle, however the exact heteroplasmy level was only reported in one of these cases at 47%. Neither case had any positive family history (PS4_supporting; PMIDs: 20884012; 21292040). This variant occurred de novo in one individual (absent in blood and muscle from mother via RFLP; PM6_supporting, PMID: 21292040). There are no large families reported in the medical literature to consider for evidence of segregation. 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 (82.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 October 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PM2_supporting, PP3, PM6_supporting.

Met criteria codes

• PM6_Supporting: This variant occurred de novo in one individual (absent in blood and muscle from mother via RFLP (PM6_supporting, PMID: 21292040).
• PP3: The computational predictor MitoTIP suggests this variant is pathogenic (82.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3).
• PS4_Supporting: The m.4308 G>A variant in MT-TI has been reported in two unrelated individuals with primary mitochondrial disease with onset ranging from the first decade to third decade of life and features include bilateral ptosis, CPEO, exercise intolerance, decreased BMI, and hyperckemia. Muscle biopsy showed ragged red fibers, COX negative fibers, and respiratory chain deficiencies across complex I, III, and IV. Both case the variant was undetectable in blood tested in their 30's and 50's. The variant was heteroplasmic in muscle, only one case reported the exact percent at 47%. Neither case had any positive family history (PS4_supporting; PMIDs: 20884012; 21292040).
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).

Not Met criteria codes

• PS3: There are no cybrids, single fiber studies, or other functional assays reported on this variant.
• PP1: There are no large families reported in the medical literature to consider for evidence of segregation.