Variant: m.5920G>A

CA120613

9669 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 9f8b39f8-d13c-432a-97d0-c2d50265f183

Approved on: 2024-01-22

Published on: 2024-03-14

HGVS expressions

NC_012920.1:m.5920G>A
J01415.2:m.5920G>A
ENST00000361624.2:c.17G>A

Likely Pathogenic

• Met criteria codes: PM2_Supporting PS3_Supporting PVS1_Strong

• Not Met criteria codes: PM6 BP4 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.5920G>A (p.W6Ter) variant in MT-CO1 has been reported in one individual to date, in a man with childhood onset myopathy, and myoglobinuria first noted in his 20s (case first reported in PMID: 10980727, also reported in PMIDs: 11506394, 11782982). His muscle biopsy showed scattered ragged red fibers (RRF) that stained intensely for SDH but not COX and numerous COX-negative/COX-deficient non-RRF. Immunohistochemistry showed markedly reduced immunostaining with antibodies to COX I and COX II, but normal reaction with antibodies to COX IV and COX VI. He had complex IV deficiency with activity being 32% controls. The variant was present at 61% heteroplasmy in muscle and was absent in blood and fibroblasts. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood from his mother and sister, however given it was also absent in the proband’s blood, it is not conclusive the variant arose de novo. There are no additional reported de novo occurrences of this variant to our knowledge. Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in loss of the last 507 amino acids (99% of the protein, PVS1_strong). Single fiber testing showed that the variant was present in all COX-deficient fibers (n=15) and that the mean mutation load in affected fibers was 65% (SD, 32.6%). The variant was only detected in six of 25 COX-positive fibers tested, and the mutational load in COX-positive fibers was 5% (SD, 11.2%; PS3_supporting; PMID: 10980727). In summary, this variant meets criteria to be classified as likely pathogenic 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 January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PVS1_strong.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PS3_Supporting: Single fiber testing showed that the variant was present in all COX-deficient fibers (n=15) and that the mean mutation load in affected fibers was 65% (SD, 32.6%). The variant was only detected in six of 25 COX-positive fibers tested, and the mutational load in COX-positive fibers was 5% (SD, 11.2%; PS3_supporting; PMID: 10980727).
• PVS1_Strong: This variant results in loss of the last 507 amino acids (99% of the protein, PVS1_strong).

Not Met criteria codes

• PM6: The variant was absent in blood from his mother and sister, however given it was also absent in the proband’s blood, it is not conclusive the variant arose de novo. There are no additional reported de novo occurrences of this variant to our knowledge.
• BP4: Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4.
• PS2: The variant was absent in blood from his mother and sister, however given it was also absent in the proband’s blood, it is not conclusive the variant arose de novo. There are no additional reported de novo occurrences of this variant to our knowledge.
• PS4: The m.5920G>A (p.W6Ter) variant in MT-CO1 has been reported in one individual to date, in a man with childhood onset myopathy, and myoglobinuria first noted in his 20s (first reported in PMID: 10980727, also reported in PMIDs: 11506394, 11782982). His muscle biopsy showed scattered ragged red fibers (RRF) that stained intensely for SDH but not COX and numerous COX-negative/COX-deficient non-RRF. Immunohistochemistry showed markedly reduced immunostaining with antibodies to COX I and COX II, but normal reaction with antibodies to COX IV and COX VI. He had complex IV deficiency with activity being 32% controls. The variant was present at 61% heteroplasmy in muscle and was absent in blood and fibroblasts. As this is the only case reported to date, PS4 could not be applied.
• PP3: Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4.