Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000234699 | SCV000285533 | uncertain significance | Werner syndrome | 2022-11-03 | 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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, |
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, |
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. |