Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000696022 | SCV000824565 | uncertain significance | Werner syndrome | 2022-10-20 | criteria provided, single submitter | clinical testing | This variant, c.1527_1532del, results in the deletion of 2 amino acid(s) of the WRN protein (p.Glu509_Glu510del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 574165). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001357949 | SCV001553562 | likely benign | not provided | no assertion criteria provided | clinical testing | The WRN p.Glu509_Glu510del variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs781777438), ClinVar (uncertain significance by Invitae with associated phenotype of Werner Syndrome), and in LOVD 3.0. The variant was also identified in control databases in 7 of 279294 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 6 of 127798 chromosomes (freq: 0.000047) and South Asian in 1 of 30268 chromosomes (freq: 0.000033); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish) and Other populations. This variant is an in-frame deletion resulting in the removal of a glutamic acid (glu) residue at codons 509 and 510 in a repeat region; the impact of this alteration on WRN protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. |