ClinVar Miner

Submissions for variant NM_003079.5(SMARCE1):c.541+1G>A

dbSNP: rs1597746020
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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 RCV000794508 SCV000933920 likely pathogenic Familial meningioma 2023-03-04 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: 641297). This variant has not been reported in the literature in individuals affected with SMARCE1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 of the SMARCE1 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 SMARCE1 are known to be pathogenic (PMID: 23377182).
Ambry Genetics RCV001024062 SCV001186016 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-20 criteria provided, single submitter clinical testing The c.541+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 6 of the SMARCE1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 splice site has a strong cryptic donor in intron 6 that, if used, is predicted to result in an in-frame inclusion of 13 amino acids with unknown functional impact. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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