Variant: NC_012920.1(MT-CYB):m.591C>T

CA913175547

1177637 (ClinVar)

Gene: MT-TF

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 97ee39c6-e5fd-4e18-97f2-2b8b2f2ac47d

Approved on: 2024-07-22

Published on: 2025-07-16

HGVS expressions

NC_012920.1:m.591C>T
J01415.2:m.591C>T

Likely Pathogenic

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: PS3 PS2 PP3 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.591C>T variant in MT-TF has been reported in individuals from five families with primary mitochondrial disease (PS4_moderate; PMID: 34607911). Affected individuals had Gitelman-like syndrome, characterized by hypokalemia and hypomagnesemia related to renal magnesium wasting and elevated renin. Additional features seen in affected individuals include paresthesia and fatigue. The variant was present at homoplasmy in affected individuals and limited unaffected individuals were tested. There are no reported de novo occurrences of this variant. This variant is absent in the MITOMAP GenBank dataset and gnomAD v3.1.2, and there are three heteroplasmic occurrences in the Helix dataset (PM2_supporting). In silico prediction tools are conflicting as MitoTIP suggests this variant is benign (7.2 percentile) however manual review has resulted in an upgraded prediction to pathogenic. Patient fibroblasts showed decreased maximal mitochondrial respiration and complex IV activity was reduced in fibroblasts from one family (PMID: 34607911). Inhibition of mitochondrial respiratory chain complex IV in HEK293 cells resulted in reduced sodium chloride cotransporter (NCC)-mediated sodium reabsorption. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent phenotype seen across affected individuals from different haplogroups and compelling functional validation. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in the MITOMAP GenBank dataset and gnomAD v3.1.2, and there are three heteroplasmic occurrences in the Helix dataset (PM2_supporting).

Not Met criteria codes

• PS3: Patient fibroblasts showed decreased maximal mitochondrial respiration and complex IV activity was reduced in fibroblasts from one family (PMID: 34607911). Inhibition of mitochondrial respiratory chain complex IV in HEK293 cells resulted in reduced sodium chloride cotransporter (NCC)-mediated sodium reabsorption.
• PS2: There are no reported de novo occurrences of this variant.
• PP3: In silico prediction tools are conflicting as MitoTIP suggests this variant is benign (7.2 percentile) however manual review has resulted in an upgraded prediction to pathogenic.
• PP1: The variant was present at homoplasmy in affected individuals and limited unaffected individuals were tested.
• PM6: There are no reported de novo occurrences of this variant.