rs28679680
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The ENST00000361624.2(MT-CO1):c.1027G>A(p.Gly343Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
MT-CO1
ENST00000361624.2 stop_gained
ENST00000361624.2 stop_gained
Scores
Clinical Significance
Multisystem-Disorder
Conservation
PhyloP100: 9.54
Genes affected
MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.334 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
No frequency data in Mitomap. Probably very rare.
PP5
?
Variant M-6930-G-A is Pathogenic according to our data. Variant chrM-6930-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9668.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COX1 | COX1.1 use as main transcript | c.1027G>A | p.Gly343Ter | stop_gained | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-CO1 | ENST00000361624.2 | c.1027G>A | p.Gly343Ter | stop_gained | 1/1 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap
Multisystem-Disorder
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
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 | Jan 22, 2024 | The m.6930G>A (p.G343Ter) variant in MT-CO1 has been reported in one individual to date, in a woman with a multisystem disorder (PMID: 10441567). Clinical features included cataracts, profound sensorineural hearing loss, myoclonic epilepsy, cerebellar ataxia, progressive muscle weakness and atrophy, progressive vision loss due to optic atrophy, and a severe sensorimotor neuropathy. Brain imaging showed diffuse cerebellar atrophy and bilateral small symmetrical nodular hyperintensities in the basal ganglia (head of the caudatus and putamen). She had elevated blood lactate (5.8 mM, normal 0.1-2.2) and CK (1000 UI/L; normal <150). Muscle biopsy showed that only 10% of fibers showed normal COX staining and her complex IV activity was 10% of controls. The variant was present at 27% heteroplasmy in blood, 75% in muscle, and 33% in myoblasts. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood from her mother, sister, and four maternal aunts (PM6_supporting). 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 170 amino acids (33% of the protein, PVS1_strong). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 10441567, 11595737). 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): PM6_supporting, PM2_supporting, PS3_supporting, PVS1_strong. - |
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1999 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
DEOGEN2
Uncertain
T
LIST_S2
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A
PROVEAN
Pathogenic
D
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at