ClinVar Miner

Submissions for variant NM_000321.2(RB1):c.1815-1G>C

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000816668 SCV000957185 uncertain significance Retinoblastoma 2018-09-25 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 18 of the RB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed as a somatic variant in an individual affected with unilateral retinoblastoma in the Leiden Open-source Variation Database (PMID: 21520333), but it has not been reported as a germline change in individuals with RB1-related disease. Additionally, this variant has been observed in an unaffected adult carrier (Invitae). Donor and acceptor splice site variants typically result in loss of protein function (PMID: 16199547), and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). Algorithms that predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site and strengthen a cryptic acceptor site in exon 19, located 18 nucleotides downstream of the natural splice site. This may result in an in-frame deletion of 6 amino acids, but otherwise preserve the integrity of the reading frame. This prediction has not been confirmed by published transcriptional studies, but suggests that the clinical significance of this splice variant may be uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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