ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1633G>T (p.Glu545Ter)

dbSNP: rs1948534542
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002402800 SCV002707618 pathogenic Hereditary cancer-predisposing syndrome 2022-03-10 criteria provided, single submitter clinical testing The p.E545* pathogenic mutation (also known as c.1633G>T), located in coding exon 17 of the RB1 gene, results from a G to T substitution at nucleotide position 1633. This changes the amino acid from a glutamic acid to a stop codon within coding exon 17. This alteration was observed in 1 of 160 patients with a diagnosis of hereditary retinoblastoma (Chaussade A et al. Eur J Med Genet, 2019 Mar;62:217-223). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with RB1-related disease (Ambry internal data). 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.
Genetics and Molecular Pathology, SA Pathology RCV001257128 SCV004175613 pathogenic Retinoblastoma 2022-11-17 criteria provided, single submitter clinical testing The RB1 c.1633G>T variant is classified as PATHOGENIC (PM2, PVS1, PM1, PS4_supporting, PP4) The RBA1 c.1633G>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 545 (PVS1). This variant is reported in dbSNP (rs1948534542), in HGMD (CM040262) and Clinvar (ClinVar ID: 966604). This variant is absent in population databases (PM2). The variant has been reported in a patient with retinoblastoma as pathogenic (PMID:14722923) and it has been detected in at least two patients with bilateral retinoblastoma (PS4_supporting). This variant is found in the retinoblastoma-associated protein A-box functional domain (PM1). The clinical features of this case are highly specific for the RB1 gene, and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4).
Labcorp Genetics (formerly Invitae), Labcorp RCV001257128 SCV004297224 pathogenic Retinoblastoma 2023-10-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu545*) 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 retinoblastoma (PMID: 14722923). This variant is also known as g.78218G>T. ClinVar contains an entry for this variant (Variation ID: 978456). For these reasons, this variant has been classified as Pathogenic.
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine RCV001257128 SCV005046155 pathogenic Retinoblastoma 2024-05-20 criteria provided, single submitter clinical testing Case and Pedigree Information: BILATERAL CASES:4, UNILATERAL CASES:1, TOTAL CASES:5, PEDIGREES:5. ACMG Codes Applied:PVS1, PM2, PS4SUP
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan RCV001257128 SCV001432963 pathogenic Retinoblastoma 2019-07-16 no assertion criteria provided clinical testing

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