Submissions for variant NM_000321.3(RB1):c.1364G>A (p.Arg455Gln)

gnomAD frequency: 0.00001  dbSNP: rs769425649

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699837	SCV000828566	uncertain significance	Retinoblastoma	2023-07-28	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 577156). This variant has not been reported in the literature in individuals affected with RB1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 455 of the RB1 protein (p.Arg455Gln). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. 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	RCV002386234	SCV002697604	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-21	criteria provided, single submitter	clinical testing	The p.R455Q variant (also known as c.1364G>A), located in coding exon 14 of the RB1 gene, results from a G to A substitution at nucleotide position 1364. The arginine at codon 455 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well 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.
Baylor Genetics	RCV003465611	SCV004208528	uncertain significance	Malignant tumor of urinary bladder	2023-07-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000699837	SCV004844665	uncertain significance	Retinoblastoma	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 455 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 been identified in 1/249800 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.