Variant: m.5874T>C

CA120538

9550 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 488953cc-e7c6-49f1-ac8f-af2f0a12a70e

Approved on: 2024-06-10

Published on: 2024-12-09

HGVS expressions

NC_012920.1:m.5874T>C
J01415.2:m.5874T>C

Uncertain Significance

• Met criteria codes: PS3_Supporting PM2_Supporting

• Not Met criteria codes: BP4 PM6 PS2 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.5874T>C variant in MT-TY has been reported in one individual with primary mitochondrial disease to date (PMIDs: 6095966, 11071502). This woman had exercise intolerance onset in childhood, muscle weakness, ptosis, and ragged red fibers on muscle biopsy. The variant was present at 89% heteroplasmy in muscle and was absent in blood. It was also absent in blood from her healthy mother and siblings, however technology at the time would not have reliably detected presence of the variant at low heteroplasmy levels. There are no other individuals with this variant reported to our knowledge. 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 benign (38.9 percentile) but HmtVAR predicts it to be deleterious with a score of 0.65. Single fiber testing showed higher levels of the variant in COX-negative fibers (92.3±6.7%; n=12) than in COX-positive fibers (29.9±11.8%; n=12; p<0.000001; PS3_supporting, PMID: 11071502). 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 June 10, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting.

Met criteria codes

• PS3_Supporting: Single fiber testing showed higher levels of the variant in COX-negative fibers (92.3±6.7%; n=12) than in COX-positive fibers (29.9±11.8%; n=12; p<0.000001; PS3_supporting, PMID: 11071502).
• 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 benign (38.9 percentile) but HmtVAR predicts it to be deleterious with a score of 0.65.
• PM6: The m.5874T>C variant in MT-TY has been reported in one individual to date (PMIDs: 6095966, 11071502). This woman had exercise intolerance onset in childhood, muscle weakness, ptosis, and ragged red fibers on muscle biopsy. The variant was present at 89% heteroplasmy in muscle and was absent in blood. It was also absent in blood from her healthy mother and siblings, however technology at the time would not have reliably detected presence of the variant at low heteroplasmy levels. There are no other individuals with this variant reported to our knowledge.
• PS2: The m.5874T>C variant in MT-TY has been reported in one individual to date (PMIDs: 6095966, 11071502). This woman had exercise intolerance onset in childhood, muscle weakness, ptosis, and ragged red fibers on muscle biopsy. The variant was present at 89% heteroplasmy in muscle and was absent in blood. It was also absent in blood from her healthy mother and siblings, however technology at the time would not have reliably detected presence of the variant at low heteroplasmy levels. There are no other individuals with this variant reported to our knowledge.
• PS4: The m.5874T>C variant in MT-TY has been reported in one individual to date (PMIDs: 6095966, 11071502). This woman had exercise intolerance onset in childhood, muscle weakness, ptosis, and ragged red fibers on muscle biopsy. The variant was present at 89% heteroplasmy in muscle and was absent in blood. It was also absent in blood from her healthy mother and siblings, however technology at the time would not have reliably detected presence of the variant at low heteroplasmy levels. There are no other individuals with this variant reported to our knowledge.
• PP3: In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is benign (38.9 percentile) but HmtVAR predicts it to be deleterious with a score of 0.65.