Variant summary: WRN c.4216C>T (p.Arg1406X) located in the last exon 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 not been observed or classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.0031 in 250856 control chromosomes, predominantly at a frequency of 0.017 within the South Asian subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in WRN causing Werner Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no penetrant association of c.4216C>T in individuals affected with Werner Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as benign/likely benign (n=4)(VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
ClinVar Genomic variation as it relates to human health
NM_000553.6(WRN):c.4216C>T (p.Arg1406Ter)
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.
(10)
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.
Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(6); Likely benign(2)
Uncertain significance(1); Benign(6); Likely benign(2)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000553.6(WRN):c.4216C>T (p.Arg1406Ter)
Variation ID: 135443 Accession: VCV000135443.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 8p12 8: 31173019 (GRCh38) [ NCBI UCSC ] 8: 31030535 (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 Jun 9, 2014 Oct 20, 2024 May 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000553.6:c.4216C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000544.2:p.Arg1406Ter nonsense NC_000008.11:g.31173019C>T NC_000008.10:g.31030535C>T NG_008870.1:g.144758C>T LRG_524:g.144758C>T LRG_524t1:c.4216C>T - Protein change
- R1406*
- Other names
- -
- Canonical SPDI
- NC_000008.11:31173018: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.
-
0.00539 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00141
The Genome Aggregation Database (gnomAD), exomes 0.00305
Exome Aggregation Consortium (ExAC) 0.00346
1000 Genomes Project 0.00539
1000 Genomes Project 30x 0.00593
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00077
The Genome Aggregation Database (gnomAD) 0.00118
- 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. |
|||
| LOC126860342 | - | - | - | GRCh38 | - | 118 |
| 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. |
|---|---|---|---|---|
| Benign (3) |
criteria provided, multiple submitters, no conflicts
|
May 4, 2022 | RCV000122300.7 | |
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000988046.15 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
May 1, 2024 | RCV001785472.15 | |
| Benign (1) |
criteria provided, single submitter
|
Jul 7, 2023 | RCV003315787.1 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548094.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: WRN c.4216C>T (p.Arg1406X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein … (more)
Variant summary: WRN c.4216C>T (p.Arg1406X) located in the last exon 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 not been observed or classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.0031 in 250856 control chromosomes, predominantly at a frequency of 0.017 within the South Asian subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in WRN causing Werner Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no penetrant association of c.4216C>T in individuals affected with Werner Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as benign/likely benign (n=4)(VUS, n=1). Based on the evidence outlined above, the variant was classified as benign. (less)
|
|
|
Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011287.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Benign
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Wiskott-Aldrich syndrome
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004016252.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
|
|
Benign
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004164600.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
WRN: BS1, BS2
Number of individuals with the variant: 4
|
|
|
Benign
(Dec 30, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000229774.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001137606.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001325808.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002028267.2
First in ClinVar: Nov 29, 2021 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 25619955, 26822949, 27153395, 27667302, 28125075)
|
|
|
Benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Werner syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000285575.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000086528.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
|
Comment:
Comment:
WRN: BS1, BS2
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant is associated with the following publications: (PMID: 25619955, 26822949, 27153395, 27667302, 28125075)
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:
Variant summary: WRN c.4216C>T (p.Arg1406X) located in the last exon 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 not been observed or classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.0031 in 250856 control chromosomes, predominantly at a frequency of 0.017 within the South Asian subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in WRN causing Werner Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no penetrant association of c.4216C>T in individuals affected with Werner Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as benign/likely benign (n=4)(VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
Comment:
WRN: BS1, BS2
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant is associated with the following publications: (PMID: 25619955, 26822949, 27153395, 27667302, 28125075)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=WRN | - | - | - | - |
| http://www.pathology.washington.edu/research/werner/database/ | - | - | - | - |
Text-mined citations for rs11574410 ...
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 Oct 20, 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.