Variant: NC_012920.1:m.5631G>A

CA274531

162369 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 8876de6c-6e67-47dd-a4a1-4859b2e0409e

Approved on: 2024-02-26

Published on: 2024-03-14

HGVS expressions

NC_012920.1:m.5631G>A
J01415.2:m.5631G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: BP4 PM6 PS4 PS2 PP1 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.5631G>A in MT-TA has been reported in one individual to date, in a woman with adult-onset myopathy (PMID: 25873012). Her muscle biopsy showed numerous COX-deficient fibers and ragged red fibers. Decreased activities of mitochondrial respiratory chain enzymes complexes I, II/III, and IV were noted although values were not provided. The variant was present in the proband at 92% in muscle, 77% in blood, 77% in hair shafts, 69% in urinary epithelial cells, and 44% in buccal sample. As this is the only case reported to date, PS4 could not be applied. Her healthy mother had the variant present at lower heteroplasmy levels (8% blood, 4% urine, 6% buccal sample) however, given no additional family members were tested, segregation evidence (PP1) could not be applied. There are no reported de novo occurrences of this variant to our knowledge. Computational predictors are conflicting precluding consideration of PP3 or BP4 (MitoTIP: 43.4%; HmtVAR: 0.45). There is one occurrence of this variant in Mitomap's 61, 134 sequences (AF=0.002%; Hg L0a); one heteroplasmic occurrence in Helix's 195,983 sequences (AF=0.001%; 10-20% heteroplasmy, Hg W); and one heteroplasmic occurrence in gnomAD v3.1.2 (0.002%; Hg V, PM2_supporting). Single fiber testing showed higher levels of the variant in COX deficient fibers (n=18; 95.1% +/- 0.45) than in COX positive fibers (n=22; 83.8% +/- 3.38; PS3_supporting, PMID: 25873012). 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 February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting.

Met criteria codes

• PM2_Supporting: This variant is present in the following databases: MITOMAP: 1 occurrence (Hg L0a), gnomAD v3.1.2: 1 heteroplasmic occurrence (10-20% heteroplasmy, Hg W), Helix: 1 heteroplasmic occurrence (Hg V).

Not Met criteria codes

• BP4: Predictors are conflicting (MitoTIP: 43.4%; HmtVAR: 0.45).
• PM6: There was a lower heteroplasmy in healthy mother and no other family members tested.
• PS4: This woman had myopathy, ptosis, and COX-deficient and ragged red fibers. The variant was present at 92% muscle, 77% blood, 77% hair shafts, 69% urinary epithelial, and 44% buccal. There is only one case reported to date with this variant.
• PS2: There was a lower heteroplasmy in healthy mother and no other family members tested.
• PP1: There was a lower heteroplasmy in healthy mother and no other family members tested.
• PP3: Predictors are conflicting (MitoTIP: 43.4%; HmtVAR: 0.45).