NM_000553.6(WRN):c.673C>T (p.Arg225Ter) AND Werner syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 2, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000473494.8

Allele description

NM_000553.6(WRN):c.673C>T (p.Arg225Ter)

Gene:

WRN:WRN RecQ like helicase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8p12

Genomic location:

Preferred name:

NM_000553.6(WRN):c.673C>T (p.Arg225Ter)

HGVS:

NC_000008.11:g.31068276C>T
NG_008870.1:g.40015C>T
NM_000553.6:c.673C>TMANE SELECT
NP_000544.2:p.Arg225Ter
LRG_524t1:c.673C>T
LRG_524:g.40015C>T
NC_000008.10:g.30925792C>T
NM_000553.4:c.673C>T

Protein change:

R225*

Links:

dbSNP: rs370324188

NCBI 1000 Genomes Browser:

rs370324188

Molecular consequence:

NM_000553.6:c.673C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Werner syndrome (WRN)
Synonyms:: Werner's syndrome
Identifiers:: MONDO: MONDO:0010196; MedGen: C0043119; Orphanet: 902; OMIM: 277700

Recent activity

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MAG: Olsenella uli isolate metabat2_pooled_hifiasm.989 MAG genome assembly, chro...
MAG: Olsenella uli isolate metabat2_pooled_hifiasm.989 MAG genome assembly, chromosome: 1
gi|2729058691|emb|OZ006991.1|

Nucleotide
MAG: uncultured Peptococcaceae bacterium isolate 6732_HOM_VAC_s129.ctg000173l_hi...
MAG: uncultured Peptococcaceae bacterium isolate 6732_HOM_VAC_s129.ctg000173l_hifiasm_large MAG genome assembly, chromosome: 1
gi|2729058704|emb|OZ007004.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000541431	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16673358, 28492532
SCV001950098	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004208846	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 3, 2023)	unknown	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

SCV000541431

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 2, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001950098

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 13, 2021)

unknown

clinical testing

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

SCV004208846

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 3, 2023)

unknown

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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The spectrum of WRN mutations in Werner syndrome patients.

Huang S, Lee L, Hanson NB, Lenaerts C, Hoehn H, Poot M, Rubin CD, Chen DF, Yang CC, Juch H, Dorn T, Spiegel R, Oral EA, Abid M, Battisti C, Lucci-Cordisco E, Neri G, Steed EH, Kidd A, Isley W, Showalter D, Vittone JL, et al.

Hum Mutat. 2006 Jun;27(6):558-67.

PubMed [citation]

PMID:: 16673358
PMCID:: PMC1868417

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000541431.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Arg225*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 404010). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001950098.1

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

Description

This variant was identified as compound heterozygous with NM_000553.6:c.3030_3033del.

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

From Baylor Genetics, SCV004208846.1

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

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

Last Updated: May 26, 2024

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