ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.4636-1G>A

dbSNP: rs1290351732
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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 RCV002007723 SCV002259352 likely pathogenic Rhabdoid tumor predisposition syndrome 2 2021-09-28 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 33 of the SMARCA4 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 SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002).
Ambry Genetics RCV004042278 SCV005038345 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-30 criteria provided, single submitter clinical testing The c.4732-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 33 of the SMARCA4 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 9 amino acids; however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). Based on the available evidence, the clinical significance of this alteration remains unclear.

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