ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4183G>A (p.Ala1395Thr) (rs1559127505)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000699236 SCV000827937 uncertain significance Early infantile epileptic encephalopathy 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1406 of the SCN1A protein (p.Ala1406Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Dravet syndrome (PMID: 21868258). 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 tolerated, 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 D3-P3 region of the resulting protein (PMID: 25348405, 18804930). The observation of one or more missense substitutions at this codon (p.Ala1406Thr and p.Ala1406Ser) in affected individuals suggests that this may be a clinically significant residue (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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