Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004791204 | SCV005407782 | pathogenic | Mitochondrial disease | 2024-02-12 | reviewed by expert panel | curation | 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. |
| OMIM | RCV000010298 | SCV000030522 | pathogenic | Mitochondrial complex IV deficiency, nuclear type 1 | 2001-09-01 | no assertion criteria provided | literature only |