Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000531975 | SCV000629337 | uncertain significance | Retinoblastoma | 2023-04-25 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 203 of the RB1 protein (p.Gly203Trp). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 458175). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). |
| Ambry Genetics | RCV002358465 | SCV002656248 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-05-04 | criteria provided, single submitter | clinical testing | The p.G203W variant (also known as c.607G>T), located in coding exon 6 of the RB1 gene, results from a G to T substitution at nucleotide position 607. The amino acid change results in glycine to tryptophan at codon 203, an amino acid with highly dissimilar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| All of Us Research Program, |
RCV000531975 | SCV004844620 | uncertain significance | Retinoblastoma | 2023-08-15 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with tryptophan at codon 203 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RB1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Baylor Genetics | RCV004568749 | SCV005054128 | uncertain significance | Malignant tumor of urinary bladder | 2024-02-11 | criteria provided, single submitter | clinical testing |