Submissions for variant NM_000553.6(WRN):c.2114C>T (p.Thr705Ile)

gnomAD frequency: 0.00017  dbSNP: rs141563618

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234699	SCV000285533	uncertain significance	Werner syndrome	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 705 of the WRN protein (p.Thr705Ile). This variant is present in population databases (rs141563618, gnomAD 0.07%). This missense change has been observed in individual(s) with abnormal lipid metabolism and/or colorectal cancer (PMID: 26344056, 32041611). ClinVar contains an entry for this variant (Variation ID: 238135). 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.
Illumina Laboratory Services, Illumina	RCV000234699	SCV001323722	uncertain significance	Werner syndrome	2017-06-05	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282074	SCV002570655	uncertain significance	not specified	2022-07-30	criteria provided, single submitter	clinical testing	Variant summary: WRN c.2114C>T (p.Thr705Ile) results in a non-conservative amino acid change located in the DEAD/DEAH box helicase domain (IPR011545) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 251388 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WRN causing Werner Syndrome (0.00036 vs 0.0025), allowing no conclusion about variant significance. c.2114C>T has been reported in the literature as a non-informative genotype in an individual with familial colorectal carcinomas of an undefined genetic basis (example, Arora_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Werner Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect despite reporting an absence of helicase activity in-vitro (Arora_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000234699	SCV005676859	uncertain significance	Werner syndrome	2024-03-29	criteria provided, single submitter	clinical testing