rs199474829
Variant summary
Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PM6_SupportingPVS1_StrongPS3_SupportingPM2_Supporting
This summary comes from the ClinGen Evidence Repository: The m.7896G>A (p.W104Ter) variant in MT-CO2 has been reported in one individual to date (PMID:11558799), in a three-year-old child with psychomotor delay, failure to thrive, and cardiac hypertrophy from infancy who later developed cerebral atrophy and pigmentary retinopathy. Complex IV deficiency was noted in muscle. The variant was present at 76% heteroplasmy in muscle, 67% in blood, and 60% in fibroblasts. The variant was undetectable in blood from her mother and sister (PM6_supporting). There are no additional individuals reported with 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). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation (52%) of the MT-CO2 protein (PVS1_strong). There were several compelling studies performed detailing functional validation (PS3_supporting). Activities and assembly of complexes I and IV (and of any COX-containing supercomplexes) were impaired in cybrid cell lines with the variant present at homoplasmy (PMID:22342700). Single fiber testing showed higher levels of the variant in COX-deficient fibers (n = 9; 70.8 ± 8.1%) than in COX-positive fibers (n = 10; 17.6 ± 17.8%; p < 0.0001; PMID:11558799). Immunoblot analysis in muscle from the proband revealed a 53% reduction of the COX II polypeptide and a 48% reduction of COX I polypeptide compared to controls (PMID:11558799). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to pathogenic given the compelling functional validation and variant type. We note that some experts on this panel felt likely pathogenic was the more appropriate classification. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM6_supporting, PS3_supporting, PM2_supporting, PVS1_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120607/MONDO:0044970/014
Frequency
Consequence
ENST00000361739.1 stop_gained
Scores
Clinical Significance
Conservation
Publications
- mitochondrial diseaseInheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
- cytochrome-c oxidase deficiency diseaseInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- MELAS syndromeInheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
- Leigh syndromeInheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 7 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| COX2 | unassigned_transcript_4802 | c.311G>A | p.Trp104* | stop_gained | Exon 1 of 1 |
Ensembl
Frequencies
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial disease Pathogenic:1
The m.7896G>A (p.W104Ter) variant in MT-CO2 has been reported in one individual to date (PMID: 11558799), in a three-year-old child with psychomotor delay, failure to thrive, and cardiac hypertrophy from infancy who later developed cerebral atrophy and pigmentary retinopathy. Complex IV deficiency was noted in muscle. The variant was present at 76% heteroplasmy in muscle, 67% in blood, and 60% in fibroblasts. The variant was undetectable in blood from her mother and sister (PM6_supporting). There are no additional individuals reported with 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). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation (52%) of the MT-CO2 protein (PVS1_strong). There were several compelling studies performed detailing functional validation (PS3_supporting). Activities and assembly of complexes I and IV (and of any COX-containing supercomplexes) were impaired in cybrid cell lines with the variant present at homoplasmy (PMID: 22342700). Single fiber testing showed higher levels of the variant in COX-deficient fibers (n = 9; 70.8 ± 8.1%) than in COX-positive fibers (n = 10; 17.6 ± 17.8%; p < 0.0001; PMID: 11558799). Immunoblot analysis in muscle from the proband revealed a 53% reduction of the COX II polypeptide and a 48% reduction of COX I polypeptide compared to controls (PMID: 11558799). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to pathogenic given the compelling functional validation and variant type. We note that some experts on this panel felt likely pathogenic was the more appropriate classification. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PM2_supporting, PVS1_strong. -
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
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Computational scores
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