Submissions for variant NM_078470.6(COX15):c.396-3C>G

gnomAD frequency: 0.00011  dbSNP: rs200910834

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000266470	SCV000329712	pathogenic	not provided	2023-03-25	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 32232962, 29431110, 12474143)
Eurofins Ntd Llc (ga)	RCV000266470	SCV000705336	uncertain significance	not provided	2017-01-05	criteria provided, single submitter	clinical testing
Invitae	RCV000266470	SCV002282245	likely pathogenic	not provided	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the COX15 gene. It does not directly change the encoded amino acid sequence of the COX15 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200910834, gnomAD 0.01%). This variant has been observed in individual(s) with mitochondrial complex IV deficiency (PMID: 12474143). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as C447-3G. ClinVar contains an entry for this variant (Variation ID: 280009). Studies have shown that this variant alters COX15 gene expression (PMID: 12474143). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469094	SCV002766264	pathogenic	Leigh syndrome	2022-11-23	criteria provided, single submitter	clinical testing	Variant summary: COX15 c.396-3C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 3' acceptor site and one predicts the variant weakens the canonical 3' acceptor site. One publication reports experimental evidence that this variant indeed affects mRNA splicing, causing a frameshift and premature truncation as a result of the skipping of exon 4 (Antonicka_2003). The variant allele was found at a frequency of 7.6e-05 in 251368 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in COX15 causing Leigh Syndrome (7.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.396-3C>G has been reported in the literature in the compound heterozygous state together with a pathogenic variant in an individual with isolated cytochrome c oxidase (COX) deficiency and early onset, fatal hypertrophic cardiomyopathy (Antonicka_2003). This individual had reduced COX activity, particularly in heart tissue, and overexpression of COX15 in cultured fibroblasts restored activity to approximately 60% of normal (Antonicka_2003). Altogether these data suggest the variant is likely associated with disease. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Two laboratories classified the variant as either pathogenic (n=1) or likely pathogenic (n=1) and one classified it as VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000006553	SCV000026736	pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2	2003-01-01	no assertion criteria provided	literature only