ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5269G>C (p.Gly1757Arg) (rs1553520227)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000636358 SCV000757797 pathogenic Early infantile epileptic encephalopathy 2018-01-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1757 of the SCN1A protein (p.Gly1757Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN1A-related disease. This variant has been observed in an individual with Dravet syndrome (Invitae). This variant identified in the SCN1A gene is located in the transmembrane spanning D4-S6 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. 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. A different variant (c.5269G>A) giving rise to the same protein effect observed here (p.Gly1757Arg) has been reported to be de novo in two individuals affected with Dravet syndrome (PMID: 27781031, 27465585), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.

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