Variant: m.622G>A

CA120551

9575 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: b527b94f-d867-4cef-b89c-21857bb60b12

Approved on: 2024-06-24

Published on: 2024-08-08

HGVS expressions

NC_012920.1:m.622G>A
J01415.2:m.622G>A

Uncertain Significance

• Met criteria codes: PS3_Supporting

• Not Met criteria codes: PS4 PP3 PM2

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.622G>A variant in MT-TF has been reported in one individual to date, in a woman with adult-onset myopathy and neuropathy. She was healthy until her early 60s when she developed exercise intolerance, fatigue, paresthesia, muscle cramps, and mild hearing impairment. Muscle biopsy showed several atrophic fibers, COX-deficient fibers, subsarcolemmal mitochondrial accumulation, and enlarged mitochondria with paracrystalline inclusions. She had reductions in complex I (50% controls), complex III (68% controls), and complex IV (55% controls) activities. The variant was present at 88% heteroplasmy in muscle, 70% in hair, 66% in urine, 63% in buccal sample, and 36% in blood (PMID: 16769874). Her mother was reported to have similar walking difficulties but did not undergo testing for this variant. Her healthy daughter had the variant present at lower heteroplasmy levels however her daughter was younger than the proband was at symptom onset. This variant is present in population databases (absent in Mitomap's GenBank sequences; one heteroplasmic and one homoplasmic occurrence in gnomAD v3.1.2; eight heteroplasmic occurrences in the Helix dataset). Single fiber testing showed higher levels of the variant in COX-negative fibers (93%±1.0; N = 11) than in COX-positive fibers (82%±8.5; N = 14), p<0.001 (PS3_supporting, PMID: 16769874). Aminoacylation defects and tRNA structural changes were also reported (PMID: 17878308). The computational predictor MitoTIP suggests this variant is neutral (41.5 percentile) and HmtVAR predicts it to be deleterious with a score of 0.7. 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 June 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting.

Met criteria codes

• PS3_Supporting: Single fiber testing showed higher levels of the variant in COX-negative fibers (93%±1.0; N = 11) than in COX-positive fibers (82%±8.5; N = 14), p<0.001 (PS3_supporting, PMID: 16769874). Aminoacylation defects and tRNA structural changes were also reported (PMID: 17878308).

Not Met criteria codes

• PS4: The m.622G>A variant in MT-TF has been reported in one individual to date, in a woman with adult-onset myopathy and neuropathy. She was healthy until her early 60s when she developed exercise intolerance, fatigue, paresthesia, muscle cramps, and mild hearing impairment. Muscle biopsy showed several atrophic fibers, COX-deficient fibers, subsarcolemmal mitochondrial accumulation, and enlarged mitochondria with paracrystalline inclusions. She had reductions in complex I (50% controls), complex III (68% controls), and complex IV (55% controls) activities. The variant was present at 88% heteroplasmy in muscle, 70% in hair, 66% in urine, 63% in buccal sample, and 36% in blood (PMID: 16769874).
• PP3: The computational predictor MitoTIP suggests this variant is neutral (41.5 percentile) and HmtVAR predicts it to be deleterious with a score of 0.7.
• PM2: This variant is present in population databases (absent in Mitomap's GenBank sequences; one heteroplasmic and one homoplasmic occurrence in gnomAD v3.1.2; eight heteroplasmic occurrences in the Helix dataset).