Submission Details

COG7, the gene encoding the conserved oligomeric Golgi (COG) complex subunit 7, was first reported in relation to autosomal recessive COG7-congenital disorders of glycosylation (COG7-CDG) in 2004 (Wu et al. 2004. PMID: 15107842). The COG complex is an evolutionarily conserved hetero-octameric protein tethering complex of the CATCHR (Complexes Associated with Tethering Containing Helical Rods) family, which controls several aspects of cellular homeostasis by orchestrating retrograde vesicle traffic within the Golgi. The COG complex interacts with all key players regulating intra-Golgi trafficking, namely SNAREs (soluble N-ethylmaleimide-sensitive, factor-attachment protein receptor), SNARE-interacting proteins, Rabs, coiled-coil tethers, and vesicular coats. COG subunit deficiencies result in the accumulation of non-tethered COG-complex dependent (CCD) vesicles, dramatic morphological and functional abnormalities of the Golgi and endosomes, and severe defects in N- and O- glycosylation, Golgi retrograde trafficking, sorting and protein secretion. Defects in seven of the eight COG subunits have been linked to severe multi-systemic diseases known as COG Congenital Disorders of Glycosylation (COG-CDG), a type II CDG (Climer et al. 2015. PMID: 26578865; Linders et al. 2020. PMID: 32629928; D'Souza et al. 2020. PMID: 32730773). COG7-CDG was discovered first (Wu et al. 2004. PMID: 15107842) and the patients may present facial structure abnormalities, winkled and loose skin, hypotonia, episodes of hyperthermia, hepatosplenomegaly, severe jaundice, recurrent infections, cardiac insufficiency, and epilepsy with the laboratory findings of CDG type II (Spaapen et al. 2005. PMID: 16151902; Morava et al. 2007. PMID: 17356545; Ng et al. 2007. PMID: 17395513; Zeevaert et al. 2009. PMID: 19577670).

To date, 13 variants in COG7 (OMIM: 606978) including missense or nonsense variants, splicing variants, small insertions/duplications, single-exon deletion, and copy number variations have been submitted to ClinVar as pathogenic or likely pathogenic. This curation includes 6 variants from eight probands in five publications (Wu et al. 2004. PMID: 15107842; Morava et al. 2007. PMID: 17356545; Ng et al. 2007. PMID: 17395513; Zeevaert et al. 2009. PMID: 19577670; Jones et al. 2011. PMID: 21811164) and four ClinVar submissions (Variation ID: 1184980 https://www.ncbi.nlm.nih.gov/clinvar/variation/1184980/; Variation ID: 1184979, https://www.ncbi.nlm.nih.gov/clinvar/variation/1184979/; Variation ID: 548708, https://www.ncbi.nlm.nih.gov/clinvar/variation/548708/; Variation ID: 548709, https://www.ncbi.nlm.nih.gov/clinvar/variation/548709/). The score for genetic evidence is 10.4 pts. The mechanism of pathogenicity appears to be loss of function.

This gene-disease relationship is also supported by experimental evidence. This includes the protein interaction of the COG7 subunit with other COG complex subunits in mammalian cells and destabilization of COG complex in HEK293T cell line lacking COG7, functional alteration in patient fibroblasts and HEK293T cell line lacking COG7, rescue of COG complex function after transfection of COG7 cDNA in patient fibroblasts and HEK293T cell line lacking COG7 (Ungar et al. 2002. PMID: 11980916; Wu et al. 2004. PMID: 15107842; Blackburn et al. 2016. PMID: 27066481). In addition, the non-human animal model of Drosophila with COG7 deficiency recapitulates the clinical and histopathological features of the disease in humans (Frappaolo et al. 2017. PMID: 28883096) (Experimental evidence – 6 points).

In summary, there is definitive evidence supporting the relationship between COG7 and autosomal recessive COG7-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on October 3, 2024 (SOP Version v11).