Variant: NC_012920.1(MT-CYB):m.618T>C

CA913175634

689818 (ClinVar)

Gene: MT-TF

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 0d13b67a-3329-4a86-9afb-6fb8aa50aa94

Approved on: 2024-09-09

Published on: 2025-05-14

HGVS expressions

NC_012920.1:m.618T>C
J01415.2:m.618T>C

Uncertain Significance

• Met criteria codes: PM2_Supporting PP3 PS3_Supporting

• Not Met criteria codes: PS4 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.618T>C variant in MT-TF has been reported in one individual with primary mitochondrial disease (PMID: 9636664). This person had myopathy with ragged red fibers on muscle biopsy and reduced activities of electron transport chain enzyme complexes I and III in muscle. The variant was present at 95% heteroplasmy in skeletal muscle and 20% in blood. The variant was undetectable in blood from his healthy sister. There are no other families or de novo occurrences of this variant reported to our knowledge. There is one heteroplasmic occurrence of this variant in the Helix dataset and this variant is absent in the MITOMAP GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (65.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3). No cybrid or single-fiber studies were performed. However, a significant loss in aminoacylation efficiency was demonstrated and, when a compensatory variant was introduced to restore Watson–Crick base pairing in the anti-codon stem, the double mutant fully restored aminoacylation (PS3_supporting; PMID: 17878308). 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 September 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting.

Met criteria codes

• PM2_Supporting: There is one heteroplasmic occurrence of this variant in the Helix dataset and this variant is absent in the MITOMAP GenBank dataset and in gnomAD v3.1.2 (PM2_supporting).
• PP3: In-silico scores were ranked in the “possibly pathogenic” range in both MitoTip, 0.658 (raw score 14.848) and HmtVar, 0.6.
• PS3_Supporting: No cybrid or single-fiber studies were performed. However, a significant loss in aminoacylation efficiency was demonstrated and when a compensatory variant was introduced to restore Watson–Crick base pairing in the anti-codon stem, the double mutant fully restored aminoacylation (PS3_supporting; PMID: 17878308).

Not Met criteria codes

• PS4: The m.618T>C variant in MT-TF has been reported in one individual with primary mitochondrial disease (PMID: 9636664). This person had myopathy with ragged red fibers on muscle biopsy and reduced activities of electron transport chain enzyme complexes I and III in muscle. The variant was present at 95% heteroplasmy in skeletal muscle and 20% in blood.
• PP1: The variant was heteroplasmic in the patient's skeletal muscle (95% mutant) and peripheral blood cells (20% mutant) but was undetectable in blood cells from his healthy sister. No other case reports were found in our review of the literature.
• PM6: No assumed de novo cases were found in our review of the literature.