COL18A1

protein-coding

collagen type XVIII alpha 1 chain, the group of MicroRNA protein coding host genes|Collagens

Gene summary

This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

Previous symbols:

MANE transcript

NM_001379500.1

Inheritance

AR, AD

ClinVar variants

P:240U:990B:737

Top phenotype

Glaucoma, primary, closed-angle; Knobloch syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr21:45,405,165-45,513,720

External References & Databases

Ensembl (ENSG00000182871)

Transcript & Mutation Effects

hg38 • Region Span ~108.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Knobloch syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800167

Submitter: Labcorp Genetics (formerly Invitae)

hereditary glaucoma, primary closed-angleLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030038

Submitter: Ambry Genetics

Knobloch syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800167

Submitter: G2P

Knobloch syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009977

Submitter: Orphanet

Knobloch syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800167

Submitter: ClinGen

Knobloch syndrome (KS) was initially described in 1972 by Knobloch and Layer (PMID:4629232) in a non consanguineous family with 5 affected members presenting with high myopia, vitreoretinal degeneration with detachment, occipital encephalocele, pendular nystagmus, reduced central vision and hypoplasia of the macula. First genotype-phenotype association was obtained in 2000 by Sertié et al. (PMID:10942434) when one homozygous splice site pathogenic variant of COL18A1 gene was detected in 12 affected individuals from a consanguineous family. One single report (PMID: 30007336) for autosomal dominant acute angle closure associated with COL18A1 variants in a family with multiple affected members was not included for the purposes of this curation. Recent data report a de novo missense variant in PAK2 gene (Antonarakis et al., 2021, PMID:33693784) in two affected siblings associated with Knobloch type 2 syndrome. COL18A1 is a heparan sulfate proteoglycan with crucial role in cell-matrix interactions that produces endostatin via proteolytic cleavage. Structurally contains 10 collagenous domains interrupted by 9 non-collagenous domains and N-terminal and C-terminal non collagenous domains. This gene has 2 promoters and produces 3 protein isoforms that differ in their N-terminal non collagenous domain. Phenotypic variability has been reported in patients carrying pathogenic variants in COL18A1 gene with most patients exhibiting ocular defects, brain malformations, developmental delay and some seizures. The mechanism of pathogenicity is biallelic inherited loss-of-function variants. Twenty five frameshift variants were reported in 48 patients across thirteen publications (PMIDs: 14695535, 35693012, 19160445, 25456301, 32178553, 27259167, 33238767, 29178892, 32700429, 33710595, 34751625, 34680907, 33449584), 1 non frameshift duplication in 1 proband (PMID:35253627), 4 splice site in 18 probands (PMIDs: 10942434, 35693012, 17546652, 27259167), 1 nonsense variant in 1 proband (PMID:34680907) and 5 missense in 8 probands (PMID: 14695535, 12707952, 35253627, 34751625, 34680907). Not all variants from the aforementioned PMIDs were scored because maximum genetic evidence points were reached. The gene-disease relationship is also supported by the phenotypic similarities of Col18a1-/- mice (PMID: 15254016), the positively co-expression of COL18A1 with other genes known to be implicated in cortical malformation syndromes (PMID: 25456301), as well as the detection of COL18A1 mRNA in in pyramidal neurons of all layers of the cortical plate (PMID: 25456301). In summary, COL18A1 is definitively associated with autosomal recessive Knobloch syndrome type 1. This has been repeatedly demonstrated and has been upheld over time. This was approved by the ClinGen Brain Malformation GCEP on 28/2/2023.

Knobloch syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009977

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Glaucoma, primary, closed-angle; Knobloch syndrome 1AD/AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Ophthalmologic

Rationale: Primary open-angle glaucoma can involve loss of vision, and awareness of disease risk may allow surveillance and early treatment; Knobloch syndrome can involve increased risk of retinal detachment, and awareness may allow early diagnosis and management

Refs: 1554013; 7802003; 10942434; 14695535; 17546652; 19160445; 20799329; 21085708; 21862674; 21937992; 30007336

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL18A1 variants in ClinVar

20 Conditions Cataloged

not providedTotal: 2857

not specifiedTotal: 528

COL18A1-related disorderTotal: 485

Inborn genetic diseasesTotal: 254

Knobloch syndromeTotal: 159

Knobloch syndrome 1Total: 67

Hereditary glaucoma, primary closed-angleTotal: 36

Retinal dystrophyTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001379500.1. 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			25 clinvar	640 clinvar	13 clinvar	678
missense		5 clinvar	932 clinvar	78 clinvar	5 clinvar	1020
nonsense	24 clinvar	12 clinvar	2 clinvar			38
start loss						0
frameshift	103 clinvar	40 clinvar	4 clinvar		1 clinvar	148
splice donor/acceptor (+/-2bp)	9 clinvar	47 clinvar	27 clinvar			83
Total	136	104	990	718	19	1967

Highest pathogenic variant AF is 0.00044272275

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001379500.1	RefSeq	NP_001366429.1	42	MANE Select
ENST00000651438.1	Ensembl	ENSP00000498485.1	42	MANE Select
NM_030582.4	RefSeq	NP_085059.2	41	Standard
NM_130444.3	RefSeq	NP_569711.2	41	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
col18a1a	Danio rerio	Structure: neural crest cell migration Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

col18a1a

Danio rerio

Structure: neural crest cell migration

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein digestion and absorption - Homo sapiens (human)
Assembly of collagen fibrils and other multimeric structures
Collagen chain trimerization
Collagen biosynthesis and modifying enzymes
Integrin cell surface interactions

Biological Process

angiogenesis
endothelial cell morphogenesis
cell adhesion
visual perception
positive regulation of cell population proliferation

Molecular Function

extracellular matrix structural constituent
extracellular matrix structural constituent conferring tensile strength
metal ion binding

Cellular Component

extracellular region
collagen trimer
basement membrane
extracellular space
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355480
Coding exons: 41
Length: 108583
Individuals with no LoFs: 124692
Homozygous LoFs: 0
Heterozygous LoFs: 119
Defined: 124811
p: 0.000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.797	1057	987	1.07	0.0000700	9439
Missense (PolyPhen)		311	300.39	1.0353		2734
Synonymous	-5.14	567	431	1.32	0.0000348	3344
Loss of Function	4.94	31	78.2	0.397	0.00000416	847

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00045	rare
Latino/Admixed American	0.00047	0.00046	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00039	0.00039	rare
Finnish	0.00015	0.00014	rare
European (Non-Finnish)	0.00054	0.00051	rare
South Asian	0.00056	0.00056	rare
Other	0.0018	0.0016	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probably plays a major role in determining the retinal structure as well as in the closure of the neural tube. {ECO:0000269|PubMed:10942434}.; FUNCTION: Endostatin: Potently inhibits endothelial cell proliferation and angiogenesis (PubMed:9459295). May inhibit angiogenesis by binding to the heparan sulfate proteoglycans involved in growth factor signaling (By similarity). Inhibits VEGFA-induced endothelial cell proliferation and migration. Seems to inhibit VEGFA-mediated signaling by blocking the interaction of VEGFA to its receptor KDR/VEGFR2. Modulates endothelial cell migration in an integrin-dependent manner implicating integrin ITGA5:ITGB1 and to a lesser extent ITGAV:ITGB3 and ITGAV:ITGB5 (By similarity). May negatively regulate the activity of homotrimeric non-collagenous domain 1 (PubMed:11257123). {ECO:0000250|UniProtKB:P39061, ECO:0000269|PubMed:11257123, ECO:0000269|PubMed:9459295}.;
Disease: DISEASE: Knobloch syndrome 1 (KNO1) [MIM:267750]: A developmental disorder primarily characterized by typical eye abnormalities, including high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects, which can range from occipital encephalocele to occult cutis aplasia. {ECO:0000269|PubMed:10942434, ECO:0000269|PubMed:23667181}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.155
RVIS EVS: 0.74
RVIS percentile EVS: 86.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.828

Gene Damage Prediction

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