Submissions for variant NM_000553.6(WRN):c.3139-1G>C

dbSNP: rs113993961

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000005780	SCV000541460	pathogenic	Werner syndrome	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 25 of the WRN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs113993961, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with Werner syndrome (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). It is commonly reported in individuals of Japanese ancestry (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). ClinVar contains an entry for this variant (Variation ID: 5447). Studies have shown that disruption of this splice site alters WRN gene expression (PMID: 10543396). Studies have shown that disruption of this splice site results in skipping of exon 26 and introduces a premature termination codon (PMID: 8602509; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000005780	SCV004208814	pathogenic	Werner syndrome	2024-02-01	criteria provided, single submitter	clinical testing
OMIM	RCV000005780	SCV000025962	pathogenic	Werner syndrome	2006-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000005780	SCV000055696	not provided	Werner syndrome		no assertion provided	literature only	Founder variant in the Japanese population; accounts for approximately 60% of variants in affected persons in this group. Results in exon 26 skipping.
SNPedia	RCV000058932	SCV000090453	not provided	not provided		no assertion provided	not provided