ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1215+1G>A (rs587776783)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492136 SCV000580776 pathogenic Hereditary cancer-predisposing syndrome 2017-03-10 criteria provided, single submitter clinical testing The c.1215+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the RB1 gene. This alteration has been reported as a germline mutation in multiple families affected with bilateral and/or unilateral retinoblastoma (Richter S et al. Am. J. Hum. Genet. 2003 Feb;72(2):253-69; Kiran V et al. Hum. Mutat. 2003 Oct;22(4):339; Houdayer C et al. Hum. Mutat. 2004 Feb;23(2):193-202; Alonso J et al. Hum. Mutat. 2005 Jan;25(1):99; Sivakumaran T et al. Hum. Mutat. 2005 Apr;25(4):396-409; Nichols K et al. Hum. Mutat. 2005 Jun;25(6):566-74; Taylor M et al. Hum. Mutat. 2007 Mar;28(3):284-93; Abouzeid H et al. Mol. Vis. 2007 Sep;13:1740-5). Analysis of RNA from an individual with bilateral retinoblastoma carrying c.1215+1G>A demonstrated that this mutation results in the skipping of coding exon 12, leading to a frameshift and a predicted alternate stop codon (Zhang K et al. Hum. Mutat. 2008 Apr;29(4):475-84). Of note, this alteration is also designated as c.1353+1G>A, IVS12+1G>A and g.70330G>A in published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000114724 SCV000629273 pathogenic Retinoblastoma 2018-08-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the RB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been observed in multiple individuals affected with retinoblastoma (PMID: 2601691, 27582626, 26396485, 16463005, 12541220) and reported to segregate with the disease at least in one family (PMID: 16463005). ClinVar contains an entry for this variant (Variation ID: 126832). Experimental studies have shown that this splice donor change causes exon 12 skipping and introduces a premature stop codon in exon 13 (PMID: 2601691). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). For these reasons, this variant has been classified as Pathogenic.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000114724 SCV000853203 pathogenic Retinoblastoma 2016-06-29 criteria provided, single submitter clinical testing This is a splice site alteration in which a G is replaced by an A at the first position in intron 12.
Fulgent Genetics,Fulgent Genetics RCV000763334 SCV000894011 pathogenic Osteosarcoma; Urinary bladder cancer; Small cell lung carcinoma; Retinoblastoma 2018-10-31 criteria provided, single submitter clinical testing
Genetics Program,Instituto Nacional de Cancer RCV000114724 SCV001478087 pathogenic Retinoblastoma 2020-08-20 criteria provided, single submitter research
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV000114724 SCV001478151 pathogenic Retinoblastoma 2020-12-15 criteria provided, single submitter research
OMIM RCV000114724 SCV000034201 pathogenic Retinoblastoma 1989-11-01 no assertion criteria provided literature only
Genetic Diagnostic Laboratory,University of Pennsylvania School of Medicine RCV000114724 SCV000087351 pathogenic Retinoblastoma 2013-09-16 no assertion criteria provided clinical testing
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan RCV000114724 SCV001432966 pathogenic Retinoblastoma 2019-10-16 no assertion criteria provided clinical testing

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