Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000477383 | SCV000541440 | uncertain significance | Werner syndrome | 2022-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 916 of the WRN protein (p.His916Pro). This variant is present in population databases (rs754985773, gnomAD 0.02%). 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: 404018). 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. |
Genetic Services Laboratory, |
RCV001821223 | SCV002071493 | uncertain significance | not specified | 2020-02-06 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the WRN gene demonstrated a sequence change, c.2747A>C, in exon 23 that results in an amino acid change, p.His916Pro. This sequence change does not appear to have been previously described in patients with WRN-related disorders and has been described in the gnomAD database with a frequency of 0.02% in European populations (dbSNP rs754985773). The p.His916Pro change affects a highly conserved amino acid residue located in a domain of the WRN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.His916Pro substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.His916Pro change remains unknown at this time. |