ClinVar Genomic variation as it relates to human health
NM_000553.6(WRN):c.1105C>T (p.Arg369Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000553.6(WRN):c.1105C>T (p.Arg369Ter)
Variation ID: 5449 Accession: VCV000005449.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 8p12 8: 31081132 (GRCh38) [ NCBI UCSC ] 8: 30938648 (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 Feb 14, 2024 Jan 17, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000553.6:c.1105C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000544.2:p.Arg369Ter nonsense NC_000008.11:g.31081132C>T NC_000008.10:g.30938648C>T NG_008870.1:g.52871C>T LRG_524:g.52871C>T LRG_524t1:c.1105C>T - Protein change
- R369*
- Other names
- R368*
- Canonical SPDI
- NC_000008.11:31081131:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00017
Exome Aggregation Consortium (ExAC) 0.00019
The Genome Aggregation Database (gnomAD) 0.00033
Trans-Omics for Precision Medicine (TOPMed) 0.00037
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 |
3620 | 3777 |
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 (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2024 | RCV000005782.28 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
May 10, 2018 | RCV000722025.2 | |
Pathogenic (3) |
criteria provided, single submitter
|
Feb 1, 2022 | RCV001546857.7 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(May 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Medulloblastoma
Affected status: yes
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000853200.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
Comment:
This is a nonsene alteration in which a C is replaced by a T at coding nucleotide 1105 and is predicted to change an Arginine … (more)
This is a nonsene alteration in which a C is replaced by a T at coding nucleotide 1105 and is predicted to change an Arginine to a premature stop codon at amino acid codon 369. Classification criteria: PVS1, PM2 (less)
Sex: female
|
|
Pathogenic
(Oct 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967690.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Arg369X variant in WRN has been reported in >20 homozygous or compound het erozygous individuals with Werner syndrome and has been reported to be … (more)
The p.Arg369X variant in WRN has been reported in >20 homozygous or compound het erozygous individuals with Werner syndrome and has been reported to be the most common variant in Caucasian patients with Werner syndrome (Oshima 1996, Matsumot o 1997, Uhrhammer 2006, Huang 2006). This variant has been identified in 0.02% ( 52/276580) of chromosomes from the general population by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and is reported in ClinVar (Variation ID: 5449). This nonsense variant leads to a premature termination cod on at position 369, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the WRN gene is an established disease mechani sm in individuals with Werner syndrome. In summary, this variant meets criteria to be classified as pathogenic for Werner syndrome in an autosomal recessive man ner based upon presence in affected individuals and predicted impact to the prot ein. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Sep 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983521.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: WRN c.1105C>T (p.Arg369X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: WRN c.1105C>T (p.Arg369X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00017 in 250884 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in WRN causing Werner Syndrome (0.00017 vs 0.0025), allowing no conclusion about variant significance. c.1105C>T has been reported in the literature in multiple individuals affected with Werner Syndrome. These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Feb 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020919.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002803567.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001766453.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31921681, 9225981, 25525159, 8968742, 27153395, 29753700, 16673358, 25182132, 25390333, 16786514, 29625052, 26689913, 31263571, 31589614, 32041611, 33077847, 33087645) (less)
|
|
Pathogenic
(Oct 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004208797.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000285510.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg369*) in the WRN gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg369*) in the WRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WRN are known to be pathogenic (PMID: 16673358). This variant is present in population databases (rs17847577, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with Werner syndrome (PMID: 8968742, 9225981, 16786514, 25182132). This variant is also known as 1336C>T and Arg368*. ClinVar contains an entry for this variant (Variation ID: 5449). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jul 01, 1997)
|
no assertion criteria provided
Method: literature only
|
WERNER SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025964.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 20, 2019 |
Comment on evidence:
In 1 Caucasian and 3 Japanese patients with Werner syndrome (WRN; 277700), Oshima et al. (1996) identified a 1336C-T transition in the WRN gene, resulting … (more)
In 1 Caucasian and 3 Japanese patients with Werner syndrome (WRN; 277700), Oshima et al. (1996) identified a 1336C-T transition in the WRN gene, resulting in an arg368-to-ter (R368X) substitution and a truncated protein lacking helicase function. Matsumoto et al. (1997) found that most Japanese patients homozygous for this mutation in exon 9 of WRN, which the authors called mutation 6, share a rare haplotype, similar to the haplotype associated with another mutation (mutation 4; 604611.0004). These results suggested that these 2 mutations arose independently in almost identical rare haplotypes. This mutation (17.5%) and mutation 4 (50.8%) accounted for approximately 70% of all mutations in 63 independent families studied. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953441.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809451.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Werner syndrome
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000055692.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Most common pathogenic variant worldwide; accounts for 20%-25% of pathogenic variants in the European and Japanese populations.
|
|
click to load more click to collapse |
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. |
Citations for germline classification of this variant
HelpTitle | 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 |
Clinical utility gene card for: Werner Syndrome--Update 2014. | Hisama FM | European journal of human genetics : EJHG | 2015 | PMID: 25182132 |
Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture. | Shimamoto A | PloS one | 2014 | PMID: 25390333 |
Werner syndrome and mutations of the WRN and LMNA genes in France. | Uhrhammer NA | Human mutation | 2006 | PMID: 16786514 |
The spectrum of WRN mutations in Werner syndrome patients. | Huang S | Human mutation | 2006 | PMID: 16673358 |
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 |
Homozygous and compound heterozygous mutations at the Werner syndrome locus. | Oshima J | Human molecular genetics | 1996 | PMID: 8968742 |
Text-mined citations for rs17847577 ...
HelpRecord last updated Mar 17, 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.