ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4319C>T (p.Ala1440Val) (rs1559122124)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000696751 SCV000825328 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2018-03-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1440 of the SCN1A protein (p.Ala1440Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Ala1440Glu) has been reported de novo in an individual affected with Dravet syndrome (PMID: 23808377). This variant identified in the SCN1A gene is located in the extracellular D3-P3 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. 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.
Research Center for Genetics and Reproductive Health,Viet Nam National University HCMC RCV001251425 SCV001160662 pathogenic Severe myoclonic epilepsy in infancy; Acute encephalopathy 2020-08-01 criteria provided, single submitter research This homozygous mutation is located in the pore-forming region (DIIIS5-S6), one of the critical functional domains of the Nav1.1 protein. In silico analysis using annotation tools including Polyphen-2, SIFT, and PROVEAN predicted the mutation to be probably damaging, damaging, and deleterious, respectively. Further analysis showed that this mutation was absent from 1000 Genomes Project database , Exome Variant Server database, and Genome Aggregation Database. Using the ACMG Standards and Guidelines 2015, this mutation was classified as "Pathogenic" (PS2, PM1, PM2, PP2, PP3 criteria applied). This mutation, in heterozygous state, has previously been reported in an 11-year-old autistic patient who had a history of seizures consistent with SCN1A (D'Gama et al., 2015). In addition, another amino acid change at the same position (p.[ala1440glu]) was also reported in a DS patient (Gaily et al., 2013).

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