ClinVar Miner

Submissions for variant NM_014191.4(SCN8A):c.615-1G>A

dbSNP: rs1555217342
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578922 SCV000681375 uncertain significance not provided 2018-01-16 criteria provided, single submitter clinical testing The c.615-1 G>A variant in the SCN8A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.615-1 G>A variant is not observed in large population cohorts (Lek et al., 2016). This splice site variant destroys the canonical splice donor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, loss-of-function is not a known mechanism of disease for the SCN8A gene. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001860018 SCV002294496 likely pathogenic Early infantile epileptic encephalopathy with suppression bursts 2022-07-25 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the SCN8A 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 SCN8A are known to be pathogenic (PMID: 19254928, 32651551). This variant is not present in population databases (gnomAD no frequency). 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: 489373). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions.

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