Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000633303 | SCV000754520 | likely pathogenic | Werner syndrome | 2018-06-20 | criteria provided, single submitter | clinical testing | This variant is an out-of-frame deletion of the genomic region encompassing exons 31-34 of the WRN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to delete 206 amino acids of the WRN protein and disrupt the amino acids encoded by the last exon. This variant has not been reported in the literature in individuals with WRN-related disease. This deletion eliminates the nuclear localization signal (NLS) motif, which is encoded by amino acids 1370-1375 in exon 34 (PMID: 9241267). Deletion of the NLS results in impaired nuclear localization of WRN protein, and therefore affects its function as a DNA helicase (PMID: 9241267, 12244128). Loss-of-function variants in WRN are known to be pathogenic (PMID: 16673358). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |