ClinVar Miner

Submissions for variant NM_000553.6(WRN):c.3130dup (p.Thr1044fs) (rs1563376595)

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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 RCV000778859 SCV000915254 uncertain significance Werner syndrome 2018-12-06 criteria provided, single submitter clinical testing The WRN c.3130dupA (p.Thr1044AsnfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Thr1044AsnfsTer5 variant has been reported in one study in which it was identified in a compound heterozygous state with a stop-gained in one individual with Werner syndrome (Huang et al. 2006). Control data are not available for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database in a region of good sequence coverage so is presumed rare. The p.Thr1044AsnfsTer5 variant is located in the functionally important RecQ helicase conserved region of the protein (Muftuoglu et al. 2008). The evidence for this variant is limited. However, due to the combination of the potential impact of frameshift variants and the evidence, the p.Thr1044AsnfsTer5 variant is classified as a variant of unknown significance but suspicious for pathogenicity for Werner syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000778859 SCV001414702 pathogenic Werner syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr1044Asnfs*5) in the WRN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Werner syndrome (PMID: 16673358). ClinVar contains an entry for this variant (Variation ID: 632026). 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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