Submissions for variant NM_003072.5(SMARCA4):c.761-2A>T

dbSNP: rs1479379455

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001026624	SCV001189044	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The c.761-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 4 in 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; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, this alteration is predicted to lead to an in-frame RNA impact and the exact functional implication is unknown at this time. This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). Based on the supporting evidence, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223106	SCV001395240	likely pathogenic	Rhabdoid tumor predisposition syndrome 2	2023-07-25	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. ClinVar contains an entry for this variant (Variation ID: 827153). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 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).
GeneDx	RCV001759716	SCV001995466	uncertain significance	not provided	2019-12-19	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of exon 5; Not observed in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV001809953	SCV002058022	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing