Variant: m.5591G>A

CA254845

9625 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: d121409e-4a12-4a99-8c07-bc9ae81fc47c

Approved on: 2024-03-11

Published on: 2025-03-19

HGVS expressions

NC_012920.1:m.5591G>A
J01415.2:m.5591G>A

Uncertain Significance

• Met criteria codes: PS3_Supporting PM2_Supporting PP3 PP1_Moderate

• Not Met criteria codes: PS4 PS2 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.5591G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease (PMIDs: 16476954, 29139113). This was a male who presented in his 40s with progressive muscle weakness, myalgia, elevated creatine kinase (CK), and lactate. Muscle biopsy noted COX deficient fibers, increased subsarcolemmal mitochondrial accumulation, and electron transport chain complexes I, III, and IV deficiency. Heteroplasmy ranged from 79% (blood) to >99% (hair shaft). This variant segregated with disease manifestations in this family as an unaffected younger brother had the variant present at 67% heteroplasmy in urine and an unaffected older brother had undetectable levels of the variant in urine (PP1_moderate; PMID: 16476954). There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (99.5%) than in COX-positive fibers (72.3%), p 0.0001 (PS3_supporting, PMID: 16476954). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PS3_supporting, PP3, PM2_supporting.

Met criteria codes

• PS3_Supporting: Single fiber testing showed higher levels of the variant in COX negative fibers (99.5%) than in COX positive fibers (72.3%), p 0.0001 (PS3_supporting, PMID: 16476954).
• 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 (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3).
• PP1_Moderate: This variant segregated with disease manifestations in this family as an unaffected younger brother had the variant present at 67% heteroplasmy in urine and an unaffected older brother had undetectable levels of the variant in urine (PP1_moderate; PMID: 16476954).

Not Met criteria codes

• PS4: The m.5591 G>A variant in MT-TA has been reported in one affected individual (PMIDs: 16476954, 29139113). The case was male who presented in his 40s with progressive muscle weakness, myalgia, elevated CK, and lactate. Muscle biopsy noted COX deficient fibers, increased subsarcolemmal mitochondrial accumulation, ETC reduction in complexes I, III, and IV. Heteroplasmy ranged from > 99% noted in hair shaft to 79% noted in blood.
• PS2: There are no reported de novo occurrences of this variant to our knowledge.
• PM6: There are no reported de novo occurrences of this variant to our knowledge.