ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5039T>A (p.Val1680Asp) (rs1553520380)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000541932 SCV000633869 likely pathogenic Early infantile epileptic encephalopathy 2019-06-23 criteria provided, single submitter clinical testing This sequence change replaces valine with aspartic acid at codon 1680 of the SCN1A protein (p.Val1680Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an SCN1A-related disease. Family studies have indicated that this variant was not present in the parents of an individual with clinical features consistent with an SCN1A-related disease, which suggests that it was de novo in that affected individual. 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. This variant identified in the SCN1A gene is located in the transmembrane spanning region D4-S5 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. In summary, this variant is a novel missense change that has been shown to arise de novo in an individual with an SCN1A-related disease. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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