ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4146T>A (p.His1382Gln) (rs772400574)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000636381 SCV000757820 uncertain significance Early infantile epileptic encephalopathy 2017-12-21 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 1393 of the SCN1A protein (p.His1393Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. 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. 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. Other missense substitution at this codon (p.His1393Pro and p.His1393Asp) has been determined to be pathogenic (PMID: 17129991, 28084635). This suggests that the histidine residue is critical for SCN1A protein function and that other missense substitutions at this position may also be pathogenic. 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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