ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.2106+2T>C

dbSNP: rs1566235515
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000696989 SCV000825576 pathogenic Retinoblastoma 2023-01-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 29662154). ClinVar contains an entry for this variant (Variation ID: 574925). Disruption of this splice site has been observed in individual(s) with retinoblastoma (PMID: 12541220, 16463005, 29662154). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 20 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).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000696989 SCV003843101 uncertain significance Retinoblastoma 2023-03-13 criteria provided, single submitter clinical testing The RB1 c.2106+2T>C intronic change results in a T to C substitution at the +2 position of intron 20 of the RB1 gene. This variant results in an aberrant transcript which removes 34 nucleotides at the 3’ end of exon 20 resulting in a frameshift and the creation of a premature stop codon (PMID: 29662154). This change is predicted to cause protein truncation or absence of the protein due to nonsense-mediated decay. This variant has been identified in individuals with a personal and/or family history of retinoblastoma (PMID: 12541220, 29662154, internal data). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.

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