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

dbSNP: rs587776783

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	RCV000114724	SCV000087351	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. ACMG Codes Applied:PVS1, PM2, PS4S
Ambry Genetics	RCV000492136	SCV000580776	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-03	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). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114724	SCV000629273	pathogenic	Retinoblastoma	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 12 of the RB1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with retinoblastoma (PMID: 2601691, 12541220, 16463005, 26396485, 27582626). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126832). Studies have shown that disruption of this splice site results in skipping of exon 12 and introduces a premature termination codon (PMID: 2601691). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000114724	SCV000853203	pathogenic	Retinoblastoma	2023-02-02	criteria provided, single submitter	clinical testing	The RB1 c.1215+1G>A intronic change results in a G to A substitution at the +1 position of intron 12 of the RB1 gene. This variant results in skipping of exon 12 resulting in nonsense-mediated decay or an abnormal protein product (PVS1). This variant has been identified in individuals with a personal and/or family history of retinoblastoma (PMID: 2601691, 12541220, 29489754, 29568217, 33456302, 34277001, internal data) and osteosarcoma (PMID: 34308366). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763334	SCV000894011	pathogenic	Bone osteosarcoma; Malignant tumor of urinary bladder; 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000114724	SCV002051260	pathogenic	Retinoblastoma	2021-12-03	criteria provided, single submitter	clinical testing	Variant summary: RB1 c.1215+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5` splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in exon 12 deletion (Dunn_1989). The variant was absent in 249940 control chromosomes (gnomAD). c.1215+1G>A has been reported in the literature in multiple individuals affected with Retinoblastoma (Dunn_1989, Richter_2002, Chai_2021). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000114724	SCV002761576	pathogenic	Retinoblastoma	2022-06-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460796	SCV004208491	pathogenic	Malignant tumor of urinary bladder	2023-10-26	criteria provided, single submitter	clinical testing
OMIM	RCV000114724	SCV000034201	pathogenic	Retinoblastoma	1989-11-01	no assertion criteria provided	literature only
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000114724	SCV001432966	pathogenic	Retinoblastoma	2019-10-16	no assertion criteria provided	clinical testing