Variant: m.5877C>T

CA254830

9552 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 7ead7323-c55f-41c8-98ee-9f037a51e56d

Approved on: 2024-06-24

Published on: 2025-04-28

HGVS expressions

NC_012920.1:m.5877C>T
J01415.2:m.5877C>T

Uncertain Significance

• Met criteria codes: PM2_Supporting PS3_Supporting

• Not Met criteria codes: PS4 PS2 PP1 PP3 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.5877C>T variant in MT-TY has been reported in one individual with primary mitochondrial disease (PMID: 11594340). This individual had proximal muscle weakness, ptosis, and external ophthalmoplegia onset at age 28 years. She also had episodic diarrhea and atrioventricular block. Muscle biopsy showed ragged red fibers and COX-negative fibers. The variant was present at 73% heteroplasmy in muscle and 0.7% in blood. The variant was present in blood from her mother who had ptosis (heteroplasmy not reported) and in her two healthy children, although they were younger than the proband at the age of symptom onset. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictors are discordant as MitoTIP suggests this variant is benign (24.8 percentile) and HmtVAR predicts it to be pathogenic (0.65). Cybrid studies support the functional impact of this variant as decreased viability and oxygen consumption were associated with higher heteroplasmy levels (PS3_supporting; PMID: 11594340). 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 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PS3_Supporting: Cybrid studies support the functional impact of this variant as decreased viability and oxygen consumption were associated with higher heteroplasmy levels (PS3_supporting; PMID: 11594340).

Not Met criteria codes

• PS4: The m.5877C>T variant in MT-TY has been reported in one individual with primary mitochondrial disease (PMID: 11594340). This individual had proximal muscle weakness, ptosis, and external ophthalmoplegia onset at age 28 years. She also had episodic diarrhea and atrioventricular block. Muscle biopsy showed ragged red fibers and COX-negative fibers. The variant was present at 73% heteroplasmy in muscle and 0.7% in blood.
• PS2: There are no reported de novo occurrences of this variant to our knowledge.
• PP1: The variant was present in blood from her mother who had ptosis (hetereoplasmy not reported) and in her two healthy children, although they were younger than the proband at the age of symptom onset.
• PP3: The computational predictors are discordant as MitoTIP suggests this variant is benign (24.8 percentile) and HmtVAR predicts it to be pathogenic (0.65).
• PM6: There are no reported de novo occurrences of this variant to our knowledge.