Submissions for variant NM_000553.6(WRN):c.2959C>T (p.Arg987Ter)

gnomAD frequency: 0.00003  dbSNP: rs747319628

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000269754	SCV000473339	likely pathogenic	Werner syndrome	2017-04-27	criteria provided, single submitter	clinical testing	The WRN c.2959C>T (p.Arg987Ter) variant is a stop-gained variant and has been reported in two individuals with Werner syndrome, including one homozygote with an atypical presentation and one compound heterozygote. The variant was also found in a heterozygous state in two unaffected family members of affected individuals (Huang et al. 2006; Takada-Watanabe et al. 2012). The variant was absent from one healthy control individual, but is reported at a frequency of 0.00002 in the total population of the Exome Aggregation Consortium. Functional studies showed that leukocytes from the homozygous individual expressed the WRN protein at approximately 40% of the level of a healthy control. COS7 cells transfected with the p.Arg987Ter variant protein showed protein localization to the cytoplasm, while the wild type protein localized exclusively to the nucleus (Takada-Watanabe et al. 2012). Based on the evidence, the p.Arg987Ter variant is classified as likely pathogenic for Werner syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000269754	SCV000629669	pathogenic	Werner syndrome	2024-09-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg987*) 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 (rs747319628, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with Werner syndrome (PMID: 16673358, 22188495). ClinVar contains an entry for this variant (Variation ID: 362809). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000269754	SCV004208811	pathogenic	Werner syndrome	2024-02-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003884511	SCV004699722	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	WRN: PVS1, PM2, PM3, PS3:Supporting