ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5222G>C (p.Cys1741Ser) (rs794726763)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000700259 SCV000829007 pathogenic Early infantile epileptic encephalopathy 2018-05-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 1741 of the SCN1A protein (p.Cys1741Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Lennox-Gastaut Syndrome (PMID: 23934111, 29186148). 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 and their clinical significance is uncertain. This variant identified in the SCN1A gene is located in the extracellular D4-P4 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. The observation of one or more missense substitutions at this codon (p.Cys1741Ser and p.Cys1741Arg) in affected individuals suggests that this may be a clinically significant residue (PMID: 23934111, 23195492). For these reasons, this variant has been classified as Pathogenic.

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