ClinVar Miner

Submissions for variant NM_000553.6(WRN):c.2959C>T (p.Arg987Ter) (rs747319628)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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.
Invitae RCV000269754 SCV000629669 pathogenic Werner syndrome 2020-06-27 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. This variant is present in population databases (rs747319628, ExAC 0.02%). This variant has been reported as homozygous or in combination with another WRN variant in individuals affected with Werner syndrome (PMID: 22188495, 16673358). Loss-of-function variants in WRN are known to be pathogenic (PMID: 16673358). For these reasons, this variant has been classified as Pathogenic.

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