ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1351C>T (p.Arg451Cys)

gnomAD frequency: 0.00001  dbSNP: rs759079385
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000697674 SCV000826299 likely benign Retinoblastoma 2025-02-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV002386221 SCV002690050 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-31 criteria provided, single submitter clinical testing The p.R451C variant (also known as c.1351C>T), located in coding exon 14 of the RB1 gene, results from a C to T substitution at nucleotide position 1351. The arginine at codon 451 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000697674 SCV003843073 uncertain significance Retinoblastoma 2023-02-28 criteria provided, single submitter clinical testing The RB1 c.1351C>T (p.Arg451Cys) missense change has a maximum founder subpopulation frequency of 0.0046% and a maximum non-founder subpopulation frequency of 0.0018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with retinoblastoma. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
All of Us Research Program, National Institutes of Health RCV000697674 SCV004844660 uncertain significance Retinoblastoma 2023-08-23 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 451 of the RB1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been identified in 3/249874 chromosomes 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.

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