Submissions for variant NM_000321.3(RB1):c.763C>T (p.Arg255Ter)

dbSNP: rs587778842

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	RCV000114712	SCV000087367	pathogenic	Retinoblastoma	2024-05-20	criteria provided, single submitter	clinical testing	Case and Pedigree Information: BILATERAL CASES:14, UNILATERAL CASES:2, TOTAL CASES:16, PEDIGREES:15. ACMG Codes Applied:PVS1, PM2, PS4M
Eurofins Ntd Llc (ga)	RCV000790825	SCV000232528	pathogenic	not provided	2014-03-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492345	SCV000580817	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-12	criteria provided, single submitter	clinical testing	The p.R255* pathogenic mutation (also known as c.763C>T), located in coding exon 8 of the RB1 gene, results from a C to T substitution at nucleotide position 763. This changes the amino acid from an arginine to a stop codon within coding exon 8. This alteration has been reported in multiple individuals with either sporadic or familial retinoblastoma (Zhang L et al. Tumour Biol. 2015 Apr;36:2409-20; Thirumalairaj K et al. J. Hum. Genet. 2015 Sep;60:547-52; Taylor M et al. Hum. Mutat. 2007 Mar;28:284-93; Rushlow D et al. Hum. Mutat. 2009 May;30:842-51; Sagi M et al. Fam. Cancer. 2015 Sep;14:471-80; Blanquet V et al. Hum. Mol. Genet. 1994 Jul;3:1185-6). Some individuals with sporadic retinoblastoma were found to be mosaic for this alteration (Rushlow D et al. Hum. Mutat. 2009 May;30:842-51; Sagi M et al. Fam. Cancer. 2015 Sep;14:471-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114712	SCV000836795	pathogenic	Retinoblastoma	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg255*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with retinoblastoma (PMID: 7704558, 22963398, 24225018, 25754945, 27155049). ClinVar contains an entry for this variant (Variation ID: 126820). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genetics Program, Instituto Nacional de Cancer	RCV000114712	SCV001478086	pathogenic	Retinoblastoma	2020-08-20	criteria provided, single submitter	research
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000114712	SCV001478148	pathogenic	Retinoblastoma	2020-12-15	criteria provided, single submitter	research
Baylor Genetics	RCV000114712	SCV002030097	pathogenic	Retinoblastoma	2021-02-09	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000790825	SCV004026187	pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2_SUP
Genetics and Molecular Pathology, SA Pathology	RCV000114712	SCV004175353	pathogenic	Retinoblastoma	2022-06-27	criteria provided, single submitter	clinical testing	The RB1 c.763C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) The RB1 c.763C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 255 (PVS1). The variant has been reported in probands with a clinical presentation of either sporadic or familial retinoblastoma (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs587778842) and in the HGMD database: CM951104. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 126820).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000790825	SCV005198043	pathogenic	not provided	2023-04-27	criteria provided, single submitter	clinical testing