NM_004385.5(VCAN):c.4004-1G>A AND Wagner syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 22, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000020591.6

Allele description [Variation Report for NM_004385.5(VCAN):c.4004-1G>A]

NM_004385.5(VCAN):c.4004-1G>A

Genes:

VCAN-AS1:VCAN antisense RNA 1 [Gene - HGNC]
VCAN:versican [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q14.3

Genomic location:

Preferred name:

NM_004385.5(VCAN):c.4004-1G>A

HGVS:

NC_000005.10:g.83537006G>A
NG_012682.1:g.70296G>A
NM_001126336.3:c.1043-8531G>A
NM_001164097.2:c.1043-1G>A
NM_001164098.2:c.4004-8531G>A
NM_004385.5:c.4004-1G>AMANE SELECT
NC_000005.9:g.82832825G>A
NM_004385.3:c.4004-1G>A
NM_004385.4:c.4004-1G>A

Nucleotide change:

IVS7AS, G-A, -1

Links:

OMIM: 118661.0005; dbSNP: rs80356554

NCBI 1000 Genomes Browser:

rs80356554

Molecular consequence:

NM_001126336.3:c.1043-8531G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001164098.2:c.4004-8531G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001164097.2:c.1043-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_004385.5:c.4004-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Wagner syndrome (WGN1)
Synonyms:: Wagner disease; Wagner vitreoretinal degeneration; Wagner syndrome type 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007740; MedGen: C1840452; Orphanet: 898; OMIM: 143200; Human Phenotype Ontology: HP:0030673

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000041078	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000058368	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2006)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002521775	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000041078

GeneReviews

no classification provided

not provided

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000058368

OMIM

no assertion criteria provided

Pathogenic
(Aug 1, 2006)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002521775

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 22, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only, clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Erosive vitreoretinopathy and wagner disease are caused by intronic mutations in CSPG2/Versican that result in an imbalance of splice variants.

Mukhopadhyay A, Nikopoulos K, Maugeri A, de Brouwer AP, van Nouhuys CE, Boon CJ, Perveen R, Zegers HA, Wittebol-Post D, van den Biesen PR, van der Velde-Visser SD, Brunner HG, Black GC, Hoyng CB, Cremers FP.

Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3565-72.

PubMed [citation]

PMID:: 16877430

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneReviews, SCV000041078.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV000058368.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of a Dutch family with Wagner vitreoretinopathy (WGVRP; 143200), Mukhopadhyay et al. (2006) identified heterozygosity for a transition in intron 7 (4004-1G-A) of the VCAN gene. The mutation was not found in unaffected members of the family, or in 250 Dutch controls. RT-PCR analysis of mutant versican transcripts showed activation of a cryptic splice site resulting in a 39-nucleotide in-frame deletion of exon 8 in splice variant V0. Quantitative PCR using RNA from patient blood samples revealed a highly significant (p less than 0.0001) and consistent increase in the V2 and V3 splice variants (more than 137-fold and more than 22-fold, respectively) compared to controls.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002521775.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000021405). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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