Variant: NC_012920.1(MT-CYB):m.578T>C

CA913175506

689805 (ClinVar)

Gene: MT-TF

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: a9cdfd5d-e0f9-460c-a03a-ffb611b954ac

Approved on: 2024-08-12

Published on: 2025-04-30

HGVS expressions

NC_012920.1:m.578T>C
J01415.2:m.578T>C

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: BP4 PS3 PS4 PP3

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.578T>C variant in MT-TF has been reported once in a cohort of individuals with primary mitochondrial disease, however clinical details were not provided precluding this case from being considered for this curation (PMID: 31965079). This variant has also been reported in monozygotic twins at low heteroplasmy levels. One twin had multiple sclerosis (MS) and one did not. Of note, MS is not considered a primary mitochondrial disease and the heteroplasmy levels were very low, so these individuals were not included in this curation (PMID: 27119776). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly pathogenic (78.3 percentile) but HmtVAR predicts it to be neutral with a score of 0.05. 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. We note one expert felt likely benign was the more appropriate classification. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).

Not Met criteria codes

• BP4: In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly pathogenic (78.3 percentile) but HmtVAR predicts it to be neutral with a score of 0.05.
• PS3: There are no cybrids, single fiber studies, or other functional assays reported on this variant.
• PS4: The m.578T>C variant in MT-TF has been reported once in a cohort of individuals with mitochondrial disease, however clinical details were not included precluding this case from being included in this curation (PMID: 31965079). This variant has also been reported in monozygotic twins at low heteroplasmy levels. One twin had multiple sclerosis (MS) and one did not. Of note, MS is not considered a primary mitochondrial disease and the heteroplasmy levels were very low, so these individuals were not included in this curation (PMID: 27119776).
• PP3: In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly pathogenic (78.3 percentile) but HmtVAR predicts it to be neutral with a score of 0.05.