ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4267C>G (p.Leu1423Val) (rs1060502190)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472521 SCV000548779 likely pathogenic Early infantile epileptic encephalopathy 2016-09-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1423 of the SCN1A protein (p.Leu1423Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN1A-related disease. Family studies indicate this missense variant likely was not inherited from either parent (i.e. occurred de novo) in an affected individual (Invitae database). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on RNA splicing and protein function that is absent from the population and has been reported as de novo in an affected individual. This evidence suggests that the variant is pathogenic, but the available data is currently insufficient to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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