Submissions for variant NM_000321.3(RB1):c.1654C>T (p.Arg552Ter)

dbSNP: rs121913303

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	RCV000114733	SCV000087356	pathogenic	Retinoblastoma	2024-05-20	criteria provided, single submitter	clinical testing	Case and Pedigree Information: BILATERAL CASES:6, UNILATERAL CASES:4, TOTAL CASES:10, PEDIGREES:10. ACMG Codes Applied:PVS1, PM2, PS4M
Invitae	RCV000114733	SCV000551833	pathogenic	Retinoblastoma	2022-12-11	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg552*) 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 premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 7704558, 22219649, 24791139, 25754945, 27582626). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 126840).
Ambry Genetics	RCV000492730	SCV000580767	pathogenic	Hereditary cancer-predisposing syndrome	2017-09-15	criteria provided, single submitter	clinical testing	The p.R552* pathogenic mutation (also known as c.1654C>T), located in coding exon 17 of the RB1 gene, results from a C to T substitution at nucleotide position 1654. This changes the amino acid from an arginine to a stop codon within coding exon 17. This alteration, often designated as "R552X" in published literature, has been detected in the germline of multiple patients diagnosed with bilateral retinoblastoma, and has been confirmed as a somatic mutation in RB tumor DNA in other patients (Braggio E et al. J Clin Pathol. 2004 Jun;57(6):585-90; Richter S et al. Am J Hum Genet. 2003 Feb;72(2):253-69; He MY et al. Mol Vis. 2014 Apr 25;20:545-52). 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.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000114733	SCV001478164	pathogenic	Retinoblastoma	2020-12-15	criteria provided, single submitter	research
Database of Curated Mutations (DoCM)	RCV000114733	SCV000504839	likely pathogenic	Retinoblastoma	2015-07-14	no assertion criteria provided	literature only
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332118	SCV004040510	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research