ClinVar Miner

Submissions for variant NM_001387283.1(SMARCA4):c.4266+1G>C

dbSNP: rs1060502086
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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 RCV000552693 SCV000648096 uncertain significance Rhabdoid tumor predisposition syndrome 2 2024-02-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 30 of the SMARCA4 gene. Loss-of-function variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002). However, tissue-specific alternative splicing of SMARCA4 gene results in functional isoforms lacking in-frame exon 30 (also known as exon 28B, PMID: 18437052). For this reason the clinical significance of loss of function variants in exon 30 is currently uncertain. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470387). 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 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.
Ambry Genetics RCV001022175 SCV001183878 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-03 criteria provided, single submitter clinical testing The c.4266+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 29 of the SMARCA4 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame loss of the 32 amino acids of coding exon 29. However, the exact functional impact of the deleted amino acids is unknown as this region of the SMARCA4 gene is excluded from other biologically relevant transcripts (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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