Submissions for variant NM_198076.6(COX20):c.157+3G>C

gnomAD frequency: 0.00066  dbSNP: rs367956888

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441332	SCV000517782	likely pathogenic	not provided	2025-02-24	criteria provided, single submitter	clinical testing	Published mRNA and protein analysis in fibroblasts from an individual with this variant demonstrated an absence of full-length mRNA and COX20 protein (PMID: 30656193); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32999401, 32606554, 32827528, 30656193, 37095481)
Undiagnosed Diseases Network, NIH	RCV001526453	SCV001736866	pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2020-12-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001526453	SCV001752704	likely pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2021-06-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000441332	SCV002255160	likely pathogenic	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the COX20 gene. It does not directly change the encoded amino acid sequence of the COX20 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367956888, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with clinical features of mitochondrial complex IV deficiency (PMID: 30656193, 32827528, 32999401). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 380082). Studies have shown that this variant alters COX20 gene expression (PMID: 30656193). 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.
Baylor Genetics	RCV001526453	SCV003835234	likely pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2022-06-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526453	SCV003934262	pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2023-05-09	criteria provided, single submitter	clinical testing	Variant summary: COX20 c.157+3G>C 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 5' splicing donor site. This impact on normal splicing was confirmed experimentally using fibroblasts from a compound heterozygous patient: only mRNA transcripts missing exon 2 could be detected, and full length COX20 mRNA transcripts were completely absent (Otero_2019). Furthermore, no protein products could be detected from these same patient fibroblasts, indicating a complete loss of protein product (Otero_2019). The variant allele was found at a frequency of 0.00057 in 249980 control chromosomes (gnomAD). c.157+3G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Mitochondrial Complex 4 Deficiency, Nuclear Type 11 (e.g. Otero_2019, Chakravorty_2020, Naess_2021). These data indicate that the variant is very likely to be associated with disease.The following publications have been ascertained in the context of this evaluation (PMID: 32999401, 32827528, 30656193). Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, four as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001526453	SCV005398921	pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex IV deficiency, nuclear type 11 (MIM#619054). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. This variant is predicted to result in an out-of- frame loss of exon 2. RT-PCR experiments using patient cells demonstrates an increased expression of the exon 2 deletion transcript and loss of the full length WT transcript compared with control cells (PMID: 30656193). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (1391 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2; 1 heterozygote, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple affected compound heterozygous individuals (ClinVar, PMIDs: 30656193). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000441332	SCV005414283	pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM3_very_strong, PS3
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001526453	SCV005914366	likely pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2022-10-20	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000763846	SCV000894775	uncertain significance	Mitochondrial complex IV deficiency, nuclear type 1	2018-10-31	flagged submission	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000441332	SCV001740199	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000441332	SCV001973233	uncertain significance	not provided		no assertion criteria provided	clinical testing
OMIM	RCV001526453	SCV002073673	pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2022-02-04	no assertion criteria provided	literature only