ClinVar Miner

Submissions for variant NM_000553.4(WRN):c.3139-1G>C (rs113993961)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000005780 SCV000055696 pathologic Werner syndrome 2011-11-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000005780 SCV000473349 pathogenic Werner syndrome 2017-04-27 criteria provided, single submitter clinical testing The WRN c.3139-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.3139-1G>C variant is reported to be the second most common variant seen in Japanese patients with Werner syndrome due to a founder effect in the Japanese population (Matsumoto et al. 1997; Huang et al. 2006). Across a selection of the available literature, the c.3139-1G>C variant has been identified in a homozygous state in 45 patients, in a compound heterozygous state in eight patients, and in a heterozygous state in eight patients (Yu et al. 1996; Matsumoto et al. 1997; Satoh et al. 1999; Huang et al. 2006). The variant was also detected in a heterozygous state in six of 1076 controls and is reported at a frequency of 0.00023 in the East Asian population of the Exome Aggregation Consortium, although this is based on only two alleles in a region of good sequencing coverage so the variant is presumed to be rare in the general population. RT-PCR experiments in patient cells have shown the variant results in the skipping of exon 26 (Yu et al. 1996). Due to the supporting evidence from the literature and the potential impact of splice acceptor variants, the c.3139-1G>C variant is classified as pathogenic for Werner syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000005780 SCV000541460 pathogenic Werner syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 25 of the WRN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs113993961, ExAC 0.02%). This variant has been reported in numerous individuals affected with Werner syndrome and it is a founder mutation for this condition in the Japanese population (PMID: 8602509, 20657174, 16673358, 27559010, 10347997). ClinVar contains an entry for this variant (Variation ID: 5447). Experimental studies have shown that this sequence change affects the expression of the WRN protein (PMID: 10543396, 8602509). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005780 SCV000025962 pathogenic Werner syndrome 2006-06-01 no assertion criteria provided literature only
SNPedia RCV000058932 SCV000090453 not provided not provided no assertion provided not provided

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