COG1

protein-coding

component of oligomeric golgi complex 1, the group of Components of oligomeric golgi complex

Gene summary

The protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. It is thought that this protein is required for steps in the normal medial and trans Golgi-associated processing of glycoconjugates and plays a role in the organization of the Golgi-localized complex. [provided by RefSeq, Jul 2008]

Previous symbols:

LDLB

MANE transcript

NM_018714.3

Inheritance

ClinVar variants

P:26U:283B:151

Top phenotype

Congenital disorder of glycosylation, type IIg

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr17:73,193,055-73,208,507

External References & Databases

Ensembl (ENSG00000166685)

Transcript & Mutation Effects

hg38 • Region Span ~15.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

COG1-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012637

Submitter: G2P

COG1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012637

Submitter: Labcorp Genetics (formerly Invitae)

COG1-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012637

Submitter: Orphanet

COG1-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012637

Submitter: ClinGen

*COG1* was first reported in relation to autosomal recessive Congenital Disorders of Glycosylation by Foulquier F, et al., in 2006 (PMID: 16537452). At least 5 unique variants, some missense and intronic variants, have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental findings. Variants in this gene have been reported in at least 5 probands from publications (PMIDs: 16537452, 19008299, 25533962, 33960418, 34625039). Mutations in *COG1* can lead to Congenital disorder of glycosylation (CDG), type Iig. CDGs result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor delay, 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. Clinical features of CDG-II caused by Cog1 deficiency include failure to thrive, generalized hypotonia, growth delay and mild psychomotor delay. No supporting segregation information is available, and the disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is supported by the biochemical function of *COG1*, the protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. Knockout of *COG1* exhibited distribution of the interaction of the subunits in the complex (PMID: 15932880). A different knockout experiment done in HEK293T displayed morphological changes in the Golgi structure, similar if not more serve changes that were previously observed in CHO cells (PMID: 27066481). Coimmunoprecipitation experiments showed interaction with other proteins in the COG complex, specifically its interaction with *COG2*, *COG3*, and *COG5 *(PMID: 11980916). In addition, the rescue of patient cells showed that overexpression of *COG1* can restore the localization of the β-1,4 galactosyltransferase (PMID: 16537452). In summary, there is strong evidence supporting this gene-disease relationship. Although additional genetic and experimental evidence is needed to establish a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. A classification of **MODERATE** was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 1/4/23 (SOP Version 10)

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IIgAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Hematologic

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

Comments: The condition can include cardiac manifestations as well as other multi-system manifestations; Hepatic-metabolized agents should be avoided

Refs: 16537452; 19008299

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COG1 variants in ClinVar

8 Conditions Cataloged

COG1 congenital disorder of glycosylationTotal: 398

Inborn genetic diseasesTotal: 167

not providedTotal: 63

not specifiedTotal: 24

COG1-related disorderTotal: 13

Prostate cancerTotal: 2

Nephrotic syndromeTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018714.3. 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	126 clinvar		129
missense			268 clinvar	23 clinvar	2 clinvar	293
nonsense	6 clinvar	5 clinvar	3 clinvar			14
start loss			1 clinvar			1
frameshift	8 clinvar	6 clinvar	2 clinvar			16
splice donor/acceptor (+/-2bp)		1 clinvar	6 clinvar			7
Total	14	12	283	149	2	460

Highest pathogenic variant AF is 0.000019705469

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018714.3	RefSeq	NP_061184.1	14	MANE Select
ENST00000299886.9	Ensembl	ENSP00000299886.4	14	MANE Select
ENST00000438720.7	Ensembl	ENSP00000400111.3	13	Standard
ENST00000582512.5	Ensembl	ENSP00000463696.1	5	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

endoplasmic reticulum to Golgi vesicle-mediated transport
intra-Golgi vesicle-mediated transport
Golgi organization
protein transport

Molecular Function

protein binding

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299886
Coding exons: 14
Length: 15518
Individuals with no LoFs: 125685
Homozygous LoFs: 0
Heterozygous LoFs: 63
Defined: 125748
p: 0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.181	537	525	1.02	0.0000306	6357
Missense (PolyPhen)		130	146.93	0.88476		1804
Synonymous	-0.444	226	218	1.04	0.0000131	1987
Loss of Function	3.43	20	44.8	0.447	0.00000250	495

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00086	0.00086	rare
Latino/Admixed American	0.00035	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for normal Golgi function. {ECO:0000250}.;
Disease: DISEASE: Congenital disorder of glycosylation 2G (CDG2G) [MIM:611209]: 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. Clinical features of CDG2G include failure to thrive, generalized hypotonia, growth retardation and mild psychomotor retardation. CDG2G is biochemically characterized by a defect in O-glycosylation as well as N-glycosylation. {ECO:0000269|PubMed:16537452}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.134

Intolerance Scores

LoFtool: 0.559
RVIS EVS: 0.03
RVIS percentile EVS: 55.84

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.933

Gene Damage Prediction

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