ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.2520G>T (p.Gly840=)

dbSNP: rs1949484533
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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 RCV001350186 SCV001544568 uncertain significance Retinoblastoma 2020-04-29 criteria provided, single submitter clinical testing 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with RB1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 840 of the RB1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RB1 protein. This variant also falls at the last nucleotide of exon 24 of the RB1 coding sequence, which is part of the consensus splice site for this exon.
Ambry Genetics RCV002456522 SCV002739212 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-03 criteria provided, single submitter clinical testing The c.2520G>T variant (also known as p.G840G), located in coding exon 24 of the RB1 gene, results from a G to T substitution at nucleotide position 2520. This nucleotide substitution does not change the at codon 840. However, this change occurs in the last base pair of coding exon 24, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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