Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001013947 | SCV001174593 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-19 | criteria provided, single submitter | clinical testing | The p.R661Q variant (also known as c.1982G>A), located in coding exon 20 of the RB1 gene, results from a G to A substitution at nucleotide position 1982. The arginine at codon 661 is replaced by glutamine, an amino acid with highly similar properties. In one study, this alteration was identified by whole exome sequencing in 1/54 patients with genetically unexplained gastric cancer (Vogelaar IP et al. Eur. J. Hum. Genet., 2017 11;25:1246-1252). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001063089 | SCV001227923 | uncertain significance | Retinoblastoma | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 661 of the RB1 protein (p.Arg661Gln). This variant is present in population databases (rs750578651, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 820461). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RB1 protein function. This variant disrupts the p.Arg661 amino acid residue in RB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1352883, 12541220, 16269091, 17096365, 24225018, 26925970). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Baylor Genetics | RCV003467613 | SCV004208506 | uncertain significance | Malignant tumor of urinary bladder | 2023-09-19 | criteria provided, single submitter | clinical testing |