RB1

Gene Facts

• HGNC Symbol: RB1 (HGNC:9884)
• HGNC Name: RB transcriptional corepressor 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: OSRC
• Alias symbols: RB, PPP1R130
• %HI: 0.53
• pLI: 1
• LOEUF: 0.24
• Cytoband: 13q14.2
• Genomic Coordinates:

  GRCh37/hg19:	chr13:48877887-49056026
  GRCh38/hg38:	chr13:48303751-48481890

• MANE Select Transcript: NM_000321.3 ENST00000267163.6
• Function: Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle (PubMed:10499802). The hypophosphorylated form binds transcription regulators of the E2F family, preventing transcription of E2F-responsive genes (PubMed:10499802). Both physically blocks E2Fs transactivating domain and recruits chromatin- modifying enzymes that actively repress transcription (PubMed:10499802). Cyclin and CDK-dependent phosphorylation of RB1 induces its dissociation from E2Fs, thereby activating tr... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-30006
• ClinGen Curation ID: CCID:007755
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 03/09/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• hereditary retinoblastoma

HI Evidence

• PUBMED: 2601691
  Dunn et al. (1989) analyzed 19 patients with RB. RB1 mutations were identified in 13 tumors, including the following germline mutations: 55 bp duplication within exon 10 (truncated protein) and a 10 bp deletion in exon 18 (truncated protein).
• PUBMED: 8651278
  Lohmann et al. (1996) reported on 119 patients with RB and found RB1 mutations in 99 patients (83%). The mutation spectrum included 42% base substitutions, 26% small length alterations, and 15% large deletions.
• PUBMED: 28575107
  Tomar et al. (2017) examined 59 RB cases, a total of 61 point mutations were identified in 84.7% (50/59) of all cases. Nonsense mutations occurred at 55.7% (34/61), followed by 24.6% (15/61) frameshift, 9.8% (6/61) splicing, 8.2% (5/61) missense and 1.64% (1/61) promoter alterations.
• PUBMED: 27126562
  Kooi et al. (2016) performed exome sequencing of 71 retinoblastomas and matched blood DNA. Aside from RB1, recurrent gene mutations were very rare. For 59/71 (83%) tumors, RB1 inactivation (either by SNV/INDEL or somatic copy number alterations detection) or high-level focal amplification of MYCN was detected. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). Their results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. They concluded that somatic variants in retinoblastoma beyond RB1 are rare and limited to copy number changes.

• HI Evidence Comments: Hereditary retinoblastoma is caused by a heterozygous germline mutation on one allele and a somatic mutation on the other allele of the RB1 gene. Per GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1452/ ): "More than 2,500 nucleotide variants have been observed in white blood cell DNA of individuals with retinoblastoma or in tumors; more than 1,700 are archived...The majority of RB1 pathogenic variants result in a premature termination codon, usually through single-base substitutions, frameshift variants, or out-of-frame exon skipping caused by splice site variants."

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity