ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.506G>A (p.Cys169Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1251503080
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001068939 SCV001234076 uncertain significance Retinoblastoma 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 169 of the RB1 protein (p.Cys169Tyr). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 862252). 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 not expected to disrupt RB1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV002339344 SCV002642882 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-31 criteria provided, single submitter clinical testing The p.C169Y variant (also known as c.506G>A), located in coding exon 5 of the RB1 gene, results from a G to A substitution at nucleotide position 506. The cysteine at codon 169 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been detected in multiple individuals with no reported features of RB1-related hereditary retinoblastoma (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

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