COG6

protein-coding

component of oligomeric golgi complex 6, the group of Components of oligomeric golgi complex

Gene summary

This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi apparatus. The encoded protein is organized with conserved oligomeric Golgi complex components 5, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

MANE transcript

NM_020751.3

Inheritance

ClinVar variants

P:45U:186B:62

Top phenotype

Congenital disorder of glycosylation, type IIl

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr13:39,655,627-39,791,666

External References & Databases

Ensembl (ENSG00000133103)

Transcript & Mutation Effects

hg38 • Region Span ~136.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

COG6-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013810

Submitter: Labcorp Genetics (formerly Invitae)

COG6-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013810

Submitter: Orphanet

hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014131

Submitter: Orphanet

COG6-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013810

Submitter: ClinGen

Component of Oligomeric Golgi Complex 6 (COG6; MIM#606977) is part of the conserved oligomeric Golgi (COG) complex involved in retrograde transport from the Golgi. Biallelic pathogenic variants in COG6 are associated with Congenital disorder of glycosylation, type III (AR; MIM#614576) and Shaheen Syndrome (AR; MIM#615328). Shaheen syndrome, originally described by Shaheen et.al, in 2013 [PMID:23606727], results from the recurrent COG6 c.1167-24A>G variant which was demonstrated by RT-PCR to result in the incorporation of intronic sequencing ultimately leading to a frameshift in approximately 75% of transcripts. While Shaheen syndrome and Congenital disorder of glycosylation, type III represent a wide range of clinical severity, the Prenatal Gene Curation Expert Panel found no difference in the inheritance pattern (autosomal recessive) nor the disease mechanism (loss of function) and have lumped these disorders under the disease entry COG6-congenital disorder of glycosylation. The first reported individuals with molecularly and functionally confirmed COG6-associated congenital disorder of glycosylation were reported in Lubbehusen , et. al. 2010 [PMID:20605848], and since its initial report, many nonsense, frameshift, canonical splice, missense, single and/or multi-exon deletions have been reported. The molecular mechanism of disease loss-of-function. Maximum points for genetic evidence was reached in individuals and families with COG6-congenital disorder of glycosylation with prenatal phenotypes commonly including oligohydramnios, intrauterine growth restriction, contractures or arthrogryposis, variable dysmorphic features including microcephaly and retrognathia, variable MRI anomalies including abnormalities of gyration and the corpus callosum, and hepatomegaly [PMID:23430903, 20605848, 26260076, 32683677, 33394555, 38278647, 35068072]. Early postnatal / infantile phenotypes in these families additionally include seizures, intracranial bleeds, thrombocytopenia, anemia, coagulopathy, hepatosplenomegaly, elevated liver enzyme with additional hepatic findings including fibrotic changes and cirrhosis, recurrent infections, failure to thrive, developmental delay, and early lethality. Cell culture models, studies in non-patient cells, and a rescue in patient cells support the role of COG6 in the COG complex, retrograde Golgi transport, and the cellular defect observed in patients with COG6-associated congenital disorder of glycosylation [PMID:21421995, 27066481, 2060584]. In summary the Prenatal Gene Curation Expert Panel has found sufficient genetic and functional evidence to classify COG6 as DEFINITIVE (Gene-Disease Validity SOPv10).

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IIlAR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Craniofacial; Dental; Dermatologic; Gastrointestinal; Hematologic; Neurologic

Intervention: Allergy/Immunology/Infectious; Hematologic

Rationale: The condition can include recurrent infections as well as other multi-systemic manifestations, and awareness may allow preventive measures as well as early and aggressive treatment of infections; A described individual presented with neurological manifestations as well as vitamin K deficiency and intracranial bleeding; 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: 20605848; 23606727

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COG6 variants in ClinVar

11 Conditions Cataloged

COG6-congenital disorder of glycosylationTotal: 191

Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndromeTotal: 146

Inborn genetic diseasesTotal: 112

not providedTotal: 72

COG6-related disorderTotal: 50

not specifiedTotal: 48

Fetal anomalies with a likely genetic causeTotal: 1

HypohidrosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020751.3. 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		1 clinvar	10 clinvar	52 clinvar	1 clinvar	64
missense	1 clinvar	1 clinvar	166 clinvar	8 clinvar	1 clinvar	177
nonsense	7 clinvar	9 clinvar	1 clinvar			17
start loss		1 clinvar				1
frameshift	5 clinvar	9 clinvar	3 clinvar			17
splice donor/acceptor (+/-2bp)	2 clinvar	9 clinvar	6 clinvar			17
Total	15	30	186	60	2	293

Highest pathogenic variant AF is 0.00002377535

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020751.3	RefSeq	NP_065802.1	19	MANE Select
ENST00000455146.8	Ensembl	ENSP00000397441.2	19	MANE Select
NM_001145079.2	RefSeq	NP_001138551.1	19	Standard
ENST00000356576.8	Ensembl	ENSP00000348983.4	3	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
protein transport
glycosylation

Molecular Function

protein binding

Cellular Component

Golgi membrane
Golgi transport complex
trans-Golgi network membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000455146
Coding exons: 19
Length: 136039
Individuals with no LoFs: 125663
Homozygous LoFs: 0
Heterozygous LoFs: 85
Defined: 125748
p: 0.000338

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.184	371	361	1.03	0.0000187	4277
Missense (PolyPhen)		120	116.42	1.0308		1371
Synonymous	0.538	121	129	0.940	0.00000656	1264
Loss of Function	1.46	29	38.8	0.748	0.00000195	469

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00038	0.00038	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00034	0.00033	rare
South Asian	0.00056	0.00056	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for normal Golgi function. {ECO:0000250}.;
Disease: DISEASE: Congenital disorder of glycosylation 2L (CDG2L) [MIM:614576]: 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 CDG2L include neonatal intractable focal seizures, vomiting, loss of consciousness, intracranial bleeding due to vitamin K deficiency, and death in infancy. {ECO:0000269|PubMed:20605848}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Shaheen syndrome (SHNS) [MIM:615328]: An autosomal recessive form of syndromic mental retardation. Affected individuals show severe intellectual disability, hypohidrosis, dental enamel hypoplasia, and hyperkeratosis of the palms and soles. Some may develop mild microcephaly. {ECO:0000269|PubMed:23606727}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.969
RVIS EVS: 0.62
RVIS percentile EVS: 83.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.747

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High