ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4057G>T (p.Val1353Phe) (rs121917954)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000700817 SCV000829589 pathogenic Early infantile epileptic encephalopathy 2018-07-18 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 1353 of the SCN1A protein (p.Val1353Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with SCN1A-related disease (Invitae). 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. The observation of one or more missense substitutions at this codon (p.Val1353Leu) in affected individuals suggests that this may be a clinically significant residue (PMID: 11254444, 14672992). This variant identified in the SCN1A gene is located in the transmembrane spanning D3-S5 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. For these reasons, this variant has been classified as Pathogenic.

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