Submissions for variant NM_000321.3(RB1):c.958C>T (p.Arg320Ter)

dbSNP: rs121913300

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	RCV000114716	SCV000087348	pathogenic	Retinoblastoma	2024-05-20	criteria provided, single submitter	clinical testing	Case and Pedigree Information: BILATERAL CASES:20, UNILATERAL CASES:2, TOTAL CASES:22, PEDIGREES:22. ACMG Codes Applied:PVS1, PM2, PS4S
Ambry Genetics	RCV000492534	SCV000580769	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	clinical testing	The p.R320* pathogenic mutation (also known as c.958C>T), located in coding exon 10 of the RB1 gene, results from a C to T substitution at nucleotide position 958. This changes the amino acid from an arginine to a stop codon within coding exon 10. This mutation has been reported in numerous individuals affected with sporadic and familial retinoblastoma both bilaterally and unilaterally (Lohmann DR et al. Am. J. Hum. Genet. 1996 May;58(5):940-9; Richter S et al. Am. J. Hum. Genet. 2003 Feb;72(2):253-69; Alonso J et al. Hum. Mutat. 2005 Jan;25(1):99; Choy KW et al. Hum. Mutat. 2002 Nov;20(5):408; Houdayer C et al. Hum. Mutat. 2004 Feb; 23(2):193-202). 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.
Invitae	RCV000114716	SCV000754146	pathogenic	Retinoblastoma	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg320*) 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 individual(s) with bilateral retinoblastoma and retinoblastoma (PMID: 7704558, 12541220, 15605413, 24225018, 24810223, 25754945, 28575107). In at least one individual the variant was observed to be de novo. This variant is also known as g.64348C>T. ClinVar contains an entry for this variant (Variation ID: 126824). For these reasons, this variant has been classified as Pathogenic.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000114716	SCV001478172	pathogenic	Retinoblastoma	2020-12-15	criteria provided, single submitter	research
GeneDx	RCV001558107	SCV001779984	pathogenic	not provided	2023-03-22	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Observed in multiple individuals with retinoblastoma (Lohmann et al., 1996; Choy et al., 2002; Alonso et al., 2005; Sagi et al., 2015; Tomar et al., 2017); This variant is associated with the following publications: (PMID: 19280657, 34190019, 8651278, 12402348, 33493472, 7704558, 28575107, 25754945, 12541220, 15605413, 27983729, 14722923, 18840911, 34308366, 34294096, 33456302, 31772335, 34277001, 34645364, 35960463, 33318192)
Genetics and Molecular Pathology, SA Pathology	RCV000114716	SCV004175605	pathogenic	Retinoblastoma	2023-03-22	criteria provided, single submitter	clinical testing	The RB1 c.958C>T variant is classified as pathogenic (PVS1, PM6, PS4, PM2, PM3) The RB1 c.958C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 320 (PVS1). This variant has been identified as a de novo variant in at least four unrelated patients (PMID:33456302) (PM6). The variant has been widely reported in patients with retinoblastoma, both as germline, somatic and mosaic(PMID:33456302, PMID:28575107) (PS4). This variant is absent from population databases (PM2). This variant has been detected in trans with a somatic pathogenic variant (PMID:28575107) (PM3). The variant has been reported in dbSNP (rs121913300) and in the HGMD database as disease causing (CM941205). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 126824) and in the RB1 variant database (LOVD RB1-000072).
Database of Curated Mutations (DoCM)	RCV000114716	SCV000504837	likely pathogenic	Retinoblastoma	2015-07-14	no assertion criteria provided	literature only