rs267606612
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong
The ENST00000362079.2(MT-CO3):c.281_295del(p.Phe94_Phe98del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
MT-CO3
ENST00000362079.2 inframe_deletion
ENST00000362079.2 inframe_deletion
Scores
Clinical Significance
Myoglobinuria
Conservation
PhyloP100: 7.73
Genes affected
MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
No frequency data in Mitomap. Probably very rare.
PM4
?
Nonframeshift variant in NON repetitive region in ENST00000362079.2.
PP5
?
Variant M-9479-TTTTTTCTTCGCAGGA-T is Pathogenic according to our data. Variant chrM-9479-TTTTTTCTTCGCAGGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9654.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COX3 | COX3.1 use as main transcript | c.281_295del | p.Phe94_Phe98del | inframe_deletion | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-CO3 | ENST00000362079.2 | c.281_295del | p.Phe94_Phe98del | inframe_deletion | 1/1 | P1 |
Frequencies
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap
Myoglobinuria
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Feb 26, 2024 | The m.9487_9501del (p.Phe94Ter) variant in MT-CO3 has been reported in one individual to date, in a teenager with myopathy and recurrent myoglobinuria (PMID: 8630495). Her muscle biopsy showed type 1 fiber predominance, many ragged red fibers (RRF) that stained heaving for SDH and were COX-negative, and 64% COX-negative fibers. Electron microscopy showed scattered areas of increased numbers of mitochondria, some of which were enlarged and irregular with disordered cristae. Complex IV activity was 14% of controls. Heteroplasmy levels were reported as 92% in muscle, 0.7% leukocytes, 0.5% in lymphocytes, and undetectable in fibroblasts. As this is the only case reported to date, PS4 could not be applied. The variant was not detected in her healthy mother’s leukocytes. However, this expert panel noted the very low heteroplasmy levels reported in the proband’s leukocytes was unusual given the technology at the time, therefore this was not considered a de novo occurrence. Given no additional family members were tested, segregation evidence (PP1) could not be applied. 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 15 base pair microdeletion results in loss of the last 167 amino acids (64% of the protein, PVS1_strong). Single fiber testing showed higher levels of the variant in COX-negative non-RRF fibers (97.4 ± 1.4%) and in COX-negative RRF (98.6 ± 0.8%) than in COX-positive fibers (25.2 ± 25.1%; PS3_supporting; PMID: 8630495). 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 February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PVS1_strong. - |
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1996 | - - |
Mitochondrial complex IV deficiency with recurrent myoglobinuria Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1996 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at