The WRN c.3139-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.3139-1G>C variant is reported to be the second most common variant seen in Japanese patients with Werner syndrome due to a founder effect in the Japanese population (Matsumoto et al. 1997; Huang et al. 2006). Across a selection of the available literature, the c.3139-1G>C variant has been identified in a homozygous state in 45 patients, in a compound heterozygous state in eight patients, and in a heterozygous state in eight patients (Yu et al. 1996; Matsumoto et al. 1997; Satoh et al. 1999; Huang et al. 2006). The variant was also detected in a heterozygous state in six of 1076 controls and is reported at a frequency of 0.00023 in the East Asian population of the Exome Aggregation Consortium, although this is based on only two alleles in a region of good sequencing coverage so the variant is presumed to be rare in the general population. RT-PCR experiments in patient cells have shown the variant results in the skipping of exon 26 (Yu et al. 1996). Due to the supporting evidence from the literature and the potential impact of splice acceptor variants, the c.3139-1G>C variant is classified as pathogenic for Werner syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000553.6(WRN):c.3139-1G>C
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000553.6(WRN):c.3139-1G>C
Variation ID: 5447 Accession: VCV000005447.14
- Type and length
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single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 8p12 8: 31141680 (GRCh38) [ NCBI UCSC ] 8: 30999196 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jun 17, 2024 Feb 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000553.6:c.3139-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000008.11:g.31141680G>C NC_000008.10:g.30999196G>C NG_008870.1:g.113419G>C LRG_524:g.113419G>C LRG_524t1:c.3139-1G>C - Protein change
- -
- Other names
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IVS25DS, G-C, -1, FS1061TER
- Canonical SPDI
- NC_000008.11:31141679:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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exon loss; Variation Ontology [ VariO:0381] PubMed: 8602509
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| WRN | - | - |
GRCh38 GRCh37 |
3647 | 3804 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000005780.21 | |
| not provided (1) |
no classification provided
|
- | RCV000058932.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000473349.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The WRN c.3139-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.3139-1G>C … (more)
The WRN c.3139-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.3139-1G>C variant is reported to be the second most common variant seen in Japanese patients with Werner syndrome due to a founder effect in the Japanese population (Matsumoto et al. 1997; Huang et al. 2006). Across a selection of the available literature, the c.3139-1G>C variant has been identified in a homozygous state in 45 patients, in a compound heterozygous state in eight patients, and in a heterozygous state in eight patients (Yu et al. 1996; Matsumoto et al. 1997; Satoh et al. 1999; Huang et al. 2006). The variant was also detected in a heterozygous state in six of 1076 controls and is reported at a frequency of 0.00023 in the East Asian population of the Exome Aggregation Consortium, although this is based on only two alleles in a region of good sequencing coverage so the variant is presumed to be rare in the general population. RT-PCR experiments in patient cells have shown the variant results in the skipping of exon 26 (Yu et al. 1996). Due to the supporting evidence from the literature and the potential impact of splice acceptor variants, the c.3139-1G>C variant is classified as pathogenic for Werner syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Dec 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000541460.8
First in ClinVar: Dec 06, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 25 of the WRN gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 25 of the WRN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs113993961, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with Werner syndrome (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). It is commonly reported in individuals of Japanese ancestry (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). ClinVar contains an entry for this variant (Variation ID: 5447). Studies have shown that disruption of this splice site alters WRN gene expression (PMID: 10543396). Studies have shown that disruption of this splice site results in skipping of exon 26 and introduces a premature termination codon (PMID: 8602509; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004208814.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 01, 2006)
|
no assertion criteria provided
Method: literature only
|
WERNER SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025962.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In a Japanese patient, born of first-cousin parents, with Werner syndrome (WRN; 277700), Yu et al. (1996) detected a homozygous G-to-C transversion in the WRN … (more)
In a Japanese patient, born of first-cousin parents, with Werner syndrome (WRN; 277700), Yu et al. (1996) detected a homozygous G-to-C transversion in the WRN gene that changed a splice donor sequence from ApG to ApC, resulting in a frameshift of codons 1078 to 1092. Individuals with Werner syndrome from 18 of 30 Japanese kindreds were found to be homozygous for this mutation; 60% of Japanese patients carried this mutation. Among mutation carriers, 12 of 16 had a 141-bp allele at a glutathione reductase (GSR2, D8S540) short-tandem repeat polymorphism (STRP), which is overrepresented in Werner syndrome patients (frequency = 0.40) and relatively rare in Japanese controls (frequency = 0.07) (Yu et al., 1994). This mutation was not observed by Yu et al. (1996) in 48 Caucasian Werner syndrome patients. Among 187 Japanese control individuals, 1 heterozygote was observed for an estimated gene frequency of 0.003, which is comparable with gene frequency estimates (0.001 to 0.005) in Japanese based on Werner syndrome prevalence rates and consanguinity estimates. In this mutation, the exon preceding the mutated splice donor sequence was missing. The premature stop codon resulting from frameshift occurred in the following exon and resulted in a predicted 1060-amino acid truncated protein. Matsumoto et al. (1997) showed that almost all the patients homozygous for this mutation, which the authors called mutation 4, shared a rare haplotype that was observed across 19 loci, extending a distance of more than 1.4 Mb across the WRN gene, consistent with the view that the loci derived from a single Japanese ancestor. This mutation (50.8%) and mutation 6 (R368X; 604611.0006; 17.5%) accounted for approximately 70% of all mutations in 63 independent families studied. Huang et al. (2006) indicated that this mutation, designated 3139-1G-C, was the second most frequent mutation in their international registry, occurring in 22 Japanese subjects and accounting for 67% of Japanese WRN cases among their registry cases. This mutation was seen exclusively in Japanese WRN patients. It resulted in deletion of exon 26 and truncation of the protein immediately after the RQC domain. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
germline
|
SNPedia
Accession: SCV000090453.1
First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Werner syndrome
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000055696.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Founder variant in the Japanese population; accounts for approximately 60% of variants in affected persons in this group. Results in exon 26 skipping.
|
Comment:
Comment:
This sequence change affects an acceptor splice site in intron 25 of the WRN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs113993961, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with Werner syndrome (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). It is commonly reported in individuals of Japanese ancestry (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). ClinVar contains an entry for this variant (Variation ID: 5447). Studies have shown that disruption of this splice site alters WRN gene expression (PMID: 10543396). Studies have shown that disruption of this splice site results in skipping of exon 26 and introduces a premature termination codon (PMID: 8602509; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
Founder variant in the Japanese population; accounts for approximately 60% of variants in affected persons in this group. Results in exon 26 skipping.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The WRN c.3139-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.3139-1G>C variant is reported to be the second most common variant seen in Japanese patients with Werner syndrome due to a founder effect in the Japanese population (Matsumoto et al. 1997; Huang et al. 2006). Across a selection of the available literature, the c.3139-1G>C variant has been identified in a homozygous state in 45 patients, in a compound heterozygous state in eight patients, and in a heterozygous state in eight patients (Yu et al. 1996; Matsumoto et al. 1997; Satoh et al. 1999; Huang et al. 2006). The variant was also detected in a heterozygous state in six of 1076 controls and is reported at a frequency of 0.00023 in the East Asian population of the Exome Aggregation Consortium, although this is based on only two alleles in a region of good sequencing coverage so the variant is presumed to be rare in the general population. RT-PCR experiments in patient cells have shown the variant results in the skipping of exon 26 (Yu et al. 1996). Due to the supporting evidence from the literature and the potential impact of splice acceptor variants, the c.3139-1G>C variant is classified as pathogenic for Werner syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This sequence change affects an acceptor splice site in intron 25 of the WRN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs113993961, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with Werner syndrome (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). It is commonly reported in individuals of Japanese ancestry (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). ClinVar contains an entry for this variant (Variation ID: 5447). Studies have shown that disruption of this splice site alters WRN gene expression (PMID: 10543396). Studies have shown that disruption of this splice site results in skipping of exon 26 and introduces a premature termination codon (PMID: 8602509; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
Founder variant in the Japanese population; accounts for approximately 60% of variants in affected persons in this group. Results in exon 26 skipping.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Werner Syndrome. | Adam MP | - | 2021 | PMID: 20301687 |
| WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects. | Yokote K | Human mutation | 2017 | PMID: 27667302 |
| Werner syndrome through the lens of tissue and tumour genomics. | Tokita M | Scientific reports | 2016 | PMID: 27559010 |
| Werner syndrome as a hereditary risk factor for exocrine pancreatic cancer: potential role of WRN in pancreatic tumorigenesis and patient-tailored therapy. | Chun SG | Cancer biology & therapy | 2010 | PMID: 20657174 |
| The spectrum of WRN mutations in Werner syndrome patients. | Huang S | Human mutation | 2006 | PMID: 16673358 |
| Immunological diagnosis of Werner syndrome by down-regulated and truncated gene products. | Goto M | Human genetics | 1999 | PMID: 10543396 |
| Prevalence of Werner's syndrome heterozygotes in Japan. | Satoh M | Lancet (London, England) | 1999 | PMID: 10347997 |
| Mutation and haplotype analyses of the Werner's syndrome gene based on its genomic structure: genetic epidemiology in the Japanese population. | Matsumoto T | Human genetics | 1997 | PMID: 9225981 |
| Positional cloning of the Werner's syndrome gene. | Yu CE | Science (New York, N.Y.) | 1996 | PMID: 8602509 |
| Linkage disequilibrium and haplotype studies of chromosome 8p 11.1-21.1 markers and Werner syndrome. | Yu CE | American journal of human genetics | 1994 | PMID: 8037212 |
Text-mined citations for rs113993961 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.