Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000586150 | SCV000698414 | pathogenic | Leigh syndrome | 2022-01-09 | criteria provided, single submitter | clinical testing | Variant summary: COX15 c.452C>G (p.Ser151X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00025 in 251510 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in COX15 causing Leigh Syndrome (0.00025 vs 0.0013), allowing no conclusion about variant significance. c.452C>G has been reported in the literature in individuals affected with Leigh Syndrome and subsequently cited by others (example, Bugiani_2005, Invernizzi_2012, Alfadhel_2011, Halperin_2020, Miryounesi_2016, de Oliveira_2021). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal complex IV activity in patient derived muscle and fibroblast samples (Bugiani 2005, Alfadhel 2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Gene |
RCV000599531 | SCV000709886 | pathogenic | not provided | 2023-09-12 | criteria provided, single submitter | clinical testing | Identified in a patient with slowly progressive Leigh syndrome with no cardiac involvement and only mild COX deficiency in muscle; this patient also harbored a likely pathogenic variant in the COX15 gene but the phase of the two variants was not reported (Bugiani et al., 2005); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21412973, 22310368, 33746038, 33171185, 15863660, 32232962, 31345219) |
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV002252173 | SCV002523890 | pathogenic | See cases | 2020-12-07 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PVS1, PS4, PM2, PM3 |
| Invitae | RCV000599531 | SCV003441592 | pathogenic | not provided | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser151*) in the COX15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COX15 are known to be pathogenic (PMID: 15863660, 21412973). This variant is present in population databases (rs149718203, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex IV deficiency (PMID: 15863660, 21412973, 33746038). This variant is also known as 503C>G (H152X). ClinVar contains an entry for this variant (Variation ID: 496238). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000033254 | SCV000057117 | pathogenic | Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 | 2011-04-01 | no assertion criteria provided | literature only |