ClinVar Miner

Submissions for variant NM_000321.2(RB1):c.1390-2A>G (rs1555286568)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000590064 SCV000696561 likely pathogenic not specified 2018-11-07 criteria provided, single submitter clinical testing Variant summary: RB1 c.1390-2A>G 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: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 29758 control chromosomes. c.1390-2A>G has been reported in the literature in one individual affected with Retinoblastoma. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000632925 SCV000754132 pathogenic Retinoblastoma 2017-11-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 14 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 reported in individuals affected with retinoblastoma (PMID: 27155049, Invitae). 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.

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