ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000013.10) (NC_000013.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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).
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.
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.
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.

Haploinsufficiency phenotype 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 ( ): "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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity