Submissions for variant NM_000321.3(RB1):c.1735C>T (p.Arg579Ter)

dbSNP: rs121913305

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	RCV000114677	SCV000087375	pathogenic	Retinoblastoma	2024-05-20	criteria provided, single submitter	clinical testing	Case and Pedigree Information: BILATERAL CASES:20, UNILATERAL CASES:3, TOTAL CASES:23, PEDIGREES:22 (one pedigree contains both unilateral and bilateral cases). ACMG Codes Applied:PVS1, PM2, PS4S
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114677	SCV000551816	pathogenic	Retinoblastoma	2023-09-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg579*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 126785). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 7704558, 12541220, 25754945, 27021801, 27582626; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV000492238	SCV000580782	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-26	criteria provided, single submitter	clinical testing	The p.R579* pathogenic mutation (also known as c.1735C>T), located in coding exon 18 of the RB1 gene, results from a C to T substitution at nucleotide position 1735. This changes the amino acid from an arginine to a stop codon within coding exon 18. This alteration has been described in many patients with bilateral and unilateral retinoblastoma and is considered a common and recurrent RB1 mutation (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; Braggio E et al. J Clin Pathol. 2004 Jun;57(6):585-90; Saliminejad K et al. J. Genet. 2013 ; 92(2):e36-40; Yousef YA et al. Fam Cancer. 2018 Apr;17(2):261-268). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000521112	SCV000617263	pathogenic	not provided	2020-02-25	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 (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 24810223, 12187430, 27021801, 21763628, 17250439, 7704558, 7795591, 23301675, 25754945, 17960112, 12541220, 15605413, 24791139, 16343894, 25157968, 28449824, 20447117, 19280657, 25236499, 23981928, 27582626, 28803391, 9311732, 26539030, 33456302)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000114677	SCV004031199	pathogenic	Retinoblastoma	2023-06-22	criteria provided, single submitter	clinical testing	The RB1 c.1735C>T (p.Arg579Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant has been identified in multiple individuals with retinoblastoma (PMID: 8651278, 12541220, 15166261, 17096365, internal data). This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000114677	SCV004175459	pathogenic	Retinoblastoma	2022-05-16	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000114677	SCV000505677	likely pathogenic	Retinoblastoma	2015-07-14	no assertion criteria provided	literature only
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000114677	SCV001432964	pathogenic	Retinoblastoma	2019-03-08	no assertion criteria provided	clinical testing