COG7

protein-coding

component of oligomeric golgi complex 7, the group of Components of oligomeric golgi complex

Gene summary

The protein encoded by this gene resides in the golgi, and constitutes one of the 8 subunits of the conserved oligomeric Golgi (COG) complex, which is required for normal golgi morphology and localization. Mutations in this gene are associated with the congenital disorder of glycosylation type IIe.[provided by RefSeq, May 2010]

MANE transcript

NM_153603.4

Inheritance

ClinVar variants

P:30U:240B:179

Top phenotype

Congenital disorder of glycosylation, type IIe

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr16:23,388,493-23,453,189

External References & Databases

Ensembl (ENSG00000168434)

Transcript & Mutation Effects

hg38 • Region Span ~64.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

COG7-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012118

Submitter: Labcorp Genetics (formerly Invitae)

COG7-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012118

Submitter: G2P

COG7-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012118

Submitter: ClinGen

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).

COG7-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012118

Submitter: Orphanet

COG7-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012118

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IIeAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic

Intervention: Hematologic

Rationale: Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized agents should be avoided

Refs: 15107842; 17356545; 19577670

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COG7 variants in ClinVar

5 Conditions Cataloged

COG7 congenital disorder of glycosylationTotal: 501

Inborn genetic diseasesTotal: 112

not providedTotal: 72

not specifiedTotal: 57

COG7-related disorderTotal: 53

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153603.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	163 clinvar	1 clinvar	167
missense		3 clinvar	232 clinvar	15 clinvar		250
nonsense	8 clinvar	3 clinvar				11
start loss	1 clinvar	1 clinvar				2
frameshift	5 clinvar	1 clinvar	2 clinvar			8
splice donor/acceptor (+/-2bp)	1 clinvar	7 clinvar	3 clinvar			11
Total	15	15	240	178	1	449

Highest pathogenic variant AF is 0.00012750183

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153603.4	RefSeq	NP_705831.1	17	MANE Select
ENST00000307149.10	Ensembl	ENSP00000305442.5	17	MANE Select
ENST00000561854.1	Ensembl	ENSP00000459872.1	3	Standard
ENST00000563164.1	Ensembl	ENSP00000460151.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification
Metabolism of proteins
Transport to the Golgi and subsequent modification

Biological Process

protein glycosylation
intracellular protein transport
endoplasmic reticulum to Golgi vesicle-mediated transport
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
Golgi organization

Molecular Function

protein binding

Cellular Component

Golgi membrane
nucleolus
Golgi apparatus
Golgi transport complex
trans-Golgi network membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307149
Coding exons: 17
Length: 64688
Individuals with no LoFs: 125653
Homozygous LoFs: 0
Heterozygous LoFs: 95
Defined: 125748
p: 0.000378

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.757	382	426	0.897	0.0000247	5069
Missense (PolyPhen)		72	107.16	0.67188		1367
Synonymous	0.375	177	183	0.965	0.0000118	1510
Loss of Function	3.26	18	40.4	0.446	0.00000213	444

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00034	0.00034	rare
South Asian	0.00075	0.00075	rare
Other	0.00081	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for normal Golgi function. {ECO:0000250}.;
Disease: DISEASE: Congenital disorder of glycosylation 2E (CDG2E) [MIM:608779]: A multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N- glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:15107842}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.743
RVIS EVS: -1.24
RVIS percentile EVS: 5.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.925

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium