Submissions for variant NM_000553.6(WRN):c.3946A>G (p.Ile1316Val)

dbSNP: rs750389299

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694986	SCV000823459	uncertain significance	Werner syndrome	2024-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1316 of the WRN protein (p.Ile1316Val). This variant is present in population databases (rs750389299, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 573335). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987668	SCV004803362	uncertain significance	not specified	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: WRN c.3946A>G (p.Ile1316Val) results in a conservative amino acid change located in the Helicase Helix-turn-helix domain (IPR029491) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 1613982 control chromosomes in the gnomAD database, including three homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in WRN causing Werner Syndrome (5.8e-05 vs 0.0025), allowing no conclusion about variant significance. However, the presence of three homozygotes is suggestive of a benign role for this variant, and at least one homozygote is 55-60 years old, which exceeds the average age of death (54 years) for individuals with Werner syndrome (GeneReviews). c.3946A>G has been reported in the literature in at least one individual referred for sequencing of loci associated with dyslipidemia and related metabolic traits, but with no clear diagnosis provided (e.g. Dron_2020). This report does not provide unequivocal conclusions about association of the variant with Werner Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32041611). ClinVar contains an entry for this variant (Variation ID: 573335). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.