ClinVar Miner

Submissions for variant NM_152743.4(BRAT1):c.1499-1G>T

dbSNP: rs1778987915
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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 RCV001260917 SCV004375498 likely pathogenic Neonatal-onset encephalopathy with rigidity and seizures 2024-10-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the BRAT1 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 BRAT1 are known to be pathogenic (PMID: 22279524, 25500575). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with BRAT1-related conditions (PMID: 33040300). ClinVar contains an entry for this variant (Variation ID: 872930). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Dr Sami Ulus Medical Genetics Department, Dr Sami Ulus Training and Research Hospital for Maternity and Children's Health and Diseases RCV001260917 SCV001237446 pathogenic Neonatal-onset encephalopathy with rigidity and seizures 2020-04-14 no assertion criteria provided clinical testing This mutation was not found in publicly available databases, including gnomAD database or among our in-house control clinical exomes. In silico predictions indicating that the variant is probably pathogenic by affecting pre-mRNA splicing were verified by genetic analysis based on reverse transcription of the patient's RNA followed by PCR amplifications and Sanger sequencing performed on cDNA. Sanger sequencing of cDNA revealed that the c.1499-1G>T variant disrupts the original acceptor splice site and activates a cryptic splice site only two nucleotides downstream of the pathogenic variant site. This change causes the deletion of the first two nucleotides of exon 12, leading to a frameshift (Glu500Alafs*36) in the mRNA of the BRAT1.

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