Variant: NC_012920.1(MT-TP):m.15958A>T

CA913175296

870596 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 44fc8280-f7dc-4ffa-b4ef-fa2999680041

Approved on: 2024-04-23

Published on: 2024-05-09

HGVS expressions

NC_012920.1:m.15958A>T
J01415.2:m.15958A>T

Uncertain Significance

• Met criteria codes: PM6_Supporting PS3_Supporting PM2_Supporting PP3

• Not Met criteria codes: PS4

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.15958A>T variant in MT-TP has been reported in one individual from one family to date (PMID: 27816331), in a boy with myopathy and failure to thrive. Muscle biopsy showed ragged red fibers, COX-deficient fibers, mitochondrial proliferation, complex I deficiency, and complex IV deficiency. The variant was present at 94% heteroplasmy in muscle, 78% in urine, 48% in skin fibroblasts, 9% in blood, and was undetectable in buccal sample. The variant was undetectable in urine, blood, and buccal sample from his mother (PM6_supporting, PMID: 27816331). The computational predictor MitoTIP suggests this variant is pathogenic (93.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.4 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (96.10% ± 1.66) than in COX positive fibers (68.78% ± 18.11), p=0.0002 (PS3_supporting, PMID: 32419253). 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 April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM6_supporting, PM2_supporting, PP3.

Met criteria codes

• PM6_Supporting: The variant was undetectable in urine, blood, and buccal sample from his mother (PM6_supporting, PMID: 27816331).
• PS3_Supporting: Single fiber testing showed higher levels of the variant in COX negative fibers (96.10% ± 1.66) than in COX positive fibers (68.78% ± 18.11), p=0.0002 (PS3_supporting, PMID: 32419253).
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PP3: The computational predictor MitoTIP suggests this variant is pathogenic (93.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.4 (PP3).

Not Met criteria codes

• PS4: The m.15958A>T variant in MT-TP has been reported in one individual from one family to date (PMID: 27816331), in a boy with myopathy and failure to thrive. Muscle biopsy showed ragged red fibers, COX-deficient fibers, mitochondrial proliferation, complex I deficiency, and complex IV deficiency. The variant was present at 94% heteroplasmy in muscle, 78% in urine, 48% in skin fibroblasts, 9% in blood, and was undetectable in buccal sample.