Variant: NC_012920.1(MT-TS1):m.7505T>C

CA261262

40885 (ClinVar)

Gene: MT-TS1

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: b5b196f2-0573-42f7-8ca5-c039e5585d1e

Approved on: 2024-08-27

Published on: 2025-04-30

HGVS expressions

NC_012920.1:m.7505T>C
J01415.2:m.7505T>C

Uncertain Significance

• Met criteria codes: PP3 PS3_Moderate PM2_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.7505T>C variant in MT-TS1 has been reported in two families with primary mitochondrial disease. Affected individuals had nonsyndromic hearing loss (PMIDs: 20153673, 33638616). The variant was present at homoplasmy in affected and unaffected family members. There are no reported de novo occurrences of this variant. There is one homoplasmic 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 (58.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Cybrid studies support the functional impact of this variant as they showed the variant was associated with decreased levels of tRNASer(UCN), altered conformation of the tRNA, altered stability of tRNASer(UCN), variable reductions of mitochondrial proteins, decreased enzymatic activities of mitochondrial respiratory chain complexes, decreased respiration, and increased reactive oxygen species (PS3_moderate; PMID: 20153673). 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 August 27, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_moderate.

Met criteria codes

• PP3: The computational predictor MitoTIP suggests this variant is pathogenic (58.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3).
• PS3_Moderate: Cybrid studies support the functional impact of this variant as they showed the variant was associated with decreased levels of tRNASer(UCN), altered conformation of the tRNA, altered stability of tRNASer(UCN), variable reductions of mitochondrial proteins, decreased enzymatic activities of mitochondrial respiratory chain complexes, decreased respiration, and increased reactive oxygen species (PS3_moderate; PMID: 20153673).
• PM2_Supporting: There is one homoplasmic 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).

Not Met criteria codes

• PS4: The m.7505T>C variant in MT-TS1 has been reported in two families with primary mitochondrial disease. Affected individuals had nonsyndromic hearing loss (PMIDs: 20153673, 33638616).
• PP1: The variant was present at homoplasmy in affected and unaffected family members.
• PM6: There are no reported de novo occurrences of this variant.