ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.138-1G>A

dbSNP: rs1593414337
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001011288 SCV001171590 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-27 criteria provided, single submitter clinical testing The c.138-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 2 of the RB1 gene. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice acceptor site, but is predicted to weaken (but not abolish) the efficiency of the native splice acceptor site by ESEfinder; however, direct evidence is unavailable. 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 likely pathogenic.
Invitae RCV003514452 SCV004297203 pathogenic Retinoblastoma 2022-11-22 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 819064). This variant is also known as 276-1G>A. Disruption of this splice site has been observed in individual(s) with retinoblastoma (PMID: 12541220, 33456302). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 of the RB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365).

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