VCAN

protein-coding

versican, the group of C-type lectin domain containing|V-set domain containing|Sushi domain containing|Hyalectan proteoglycans

Gene summary

This gene is a member of the aggrecan/versican proteoglycan family. The protein encoded is a large chondroitin sulfate proteoglycan and is a major component of the extracellular matrix. This protein is involved in cell adhesion, proliferation, proliferation, migration and angiogenesis and plays a central role in tissue morphogenesis and maintenance. Mutations in this gene are the cause of Wagner syndrome type 1. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

Previous symbols:

CSPG2

MANE transcript

NM_004385.5

Inheritance

ClinVar variants

P:25U:1540B:739

Top phenotype

Wagner vitreoretinopathy

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr5:83,471,618-83,582,303

External References & Databases

Ensembl (ENSG00000038427)

Transcript & Mutation Effects

hg38 • Region Span ~110.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Wagner diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007740

Submitter: ClinGen

Variants in VCAN have been reported in multiple families affected by autosomal dominant Wagner disease since 2005 (Miyamoto et al., PMID 16043844). At least six splicing variants in intron 7 (transcript NM_004385.5) have been reported in humans, often in large families segregating perfectly with the disease. More evidence including additional splicing variants in intron 7 and large deletions involving exon 8 is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is further supported by expression studies showing that VCAN is expressed in the eye. In summary, VCAN is definitively associated with autosomal dominant Wagner disease.

Wagner diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007740

Submitter: Orphanet

Wagner diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007740

Submitter: Ambry Genetics

Wagner diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007740

Submitter: G2P

Wagner diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007740

Submitter: Labcorp Genetics (formerly Invitae)

Wagner diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007740

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Wagner vitreoretinopathyAD

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 9098284; 16043844; 16636652; 19901218; 20301747; 21738396; 22739342

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VCAN variants in ClinVar

14 Conditions Cataloged

not providedTotal: 2161

Inborn genetic diseasesTotal: 454

VitreoretinopathyTotal: 162

Wagner diseaseTotal: 114

VCAN-related disorderTotal: 92

not specifiedTotal: 38

Retinal dystrophyTotal: 17

Retinitis pigmentosaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004385.5. 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			17 clinvar	546 clinvar	42 clinvar	605
missense		2 clinvar	1501 clinvar	131 clinvar	20 clinvar	1654
nonsense	4 clinvar	1 clinvar	6 clinvar			11
start loss						0
frameshift	3 clinvar	3 clinvar	9 clinvar			15
splice donor/acceptor (+/-2bp)	10 clinvar	2 clinvar	7 clinvar			19
Total	17	8	1540	677	62	2304

Highest pathogenic variant AF is 0.00005329222

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004385.5	RefSeq	NP_004376.2	14	MANE Select
ENST00000265077.8	Ensembl	ENSP00000265077.3	14	MANE Select
NM_001126336.3	RefSeq	NP_001119808.1	12	Standard
NM_001164097.2	RefSeq	NP_001157569.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
vcana	Danio rerio	Structure: pronephric podocyte Quality: increased width abnormal

Gene / Model

Organism

Observed Phenotype

vcana

Danio rerio

Structure: pronephric podocyte

Quality: increased width

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell adhesion molecules (CAMs) - Homo sapiens (human)
Spinal Cord Injury
Hair Follicle Development- Induction (Part 1 of 3)
Metabolism of carbohydrates
Post-translational protein phosphorylation

Biological Process

skeletal system development
osteoblast differentiation
cell adhesion
multicellular organism development
central nervous system development

Molecular Function

calcium ion binding
protein binding
glycosaminoglycan binding
hyaluronic acid binding
extracellular matrix structural constituent conferring compression resistance

Cellular Component

extracellular region
extracellular space
endoplasmic reticulum lumen
Golgi lumen
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265077
Coding exons: 14
Length: 110839
Individuals with no LoFs: 125636
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125638
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.139	1708	1.72e+3	0.991	0.0000896	22173
Missense (PolyPhen)		291	370.08	0.78632		4484
Synonymous	-0.179	637	631	1.01	0.0000352	6862
Loss of Function	8.27	13	104	0.125	0.00000510	1490

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in intercellular signaling and in connecting cells with the extracellular matrix. May take part in the regulation of cell motility, growth and differentiation. Binds hyaluronic acid.;
Disease: DISEASE: Wagner vitreoretinopathy (WGVRP) [MIM:143200]: A rare vitreoretinopathy characterized by an optically empty vitreous cavity with fibrillary condensations and a preretinal avascular membrane. Other optical features include progressive chorioretinal atrophy, perivascular sheating, subcapsular cataract and myopia. {ECO:0000269|PubMed:16043844, ECO:0000269|PubMed:22739342}. Note=The disease is caused by mutations affecting the gene represented in this entry. The pathological mechanism involves a quantitave imbalance of the normally occurring splice variants (PubMed:22739342). {ECO:0000269|PubMed:22739342}.;

Recessive Scores

pRec: 0.747

Intolerance Scores

LoFtool: 0.00813
RVIS EVS: -0.55
RVIS percentile EVS: 19.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.683

Gene Damage Prediction

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