Submissions for variant NM_000553.6(WRN):c.2665C>T (p.Arg889Ter)

gnomAD frequency: 0.00002  dbSNP: rs774765029

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456191	SCV000541469	pathogenic	Werner syndrome	2024-03-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg889*) 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 (rs774765029, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Werner syndrome (PMID: 8968742, 9012406, 16673358, 16786514). ClinVar contains an entry for this variant (Variation ID: 404045). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000456191	SCV004208810	pathogenic	Werner syndrome	2024-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000456191	SCV004241254	pathogenic	Werner syndrome	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: WRN c.2665C>T (p.Arg889X) 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. The variant allele was found at a frequency of 2.4e-05 in 251074 control chromosomes. c.2665C>T has been reported in the literature in multiple individuals affected with Werner Syndrome (eg. Huang_2006). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001580038	SCV005042520	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	WRN: PVS1, PM2:Supporting, PS3:Supporting
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001580038	SCV001809447	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001580038	SCV001966582	pathogenic	not provided		no assertion criteria provided	clinical testing