Submissions for variant NM_001040142.2(SCN2A):c.3631G>A (p.Glu1211Lys)

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Total submissions: 10

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795937	SCV005417063	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11; Episodic ataxia, type 9		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Supporting+PS2+PP4+PP3_Moderate+PP2
Neuberg Centre For Genomic Medicine, NCGM	RCV000022767	SCV004048337	pathogenic	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing	The amino acid Glu at position 1211 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported in individuals with clinical features of early infantile epileptic encephalopathy (Ogiwara et al, 2009, Lee et al, 2014). Experimental studies have shown that this missense change significantly changed the functional property of the sodium channels leading to both augmented and reduced channel activities by electrophysiological analyses in the cells (Ogiwara et al, 2009). The p.Glu1211Lys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Glu1211Lys in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000022767	SCV004013955	pathogenic	Developmental and epileptic encephalopathy, 11	2022-09-28	criteria provided, single submitter	clinical testing	PM2, PP3, PP5
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806278	SCV000946267	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1211 of the SCN2A protein (p.Glu1211Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 19786696, 25326637, 25459969, 28379373). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29886). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN2A function (PMID: 19786696). For these reasons, this variant has been classified as Pathogenic.
UCLA Clinical Genomics Center, UCLA	RCV000022767	SCV000255458	likely pathogenic	Developmental and epileptic encephalopathy, 11	2013-07-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000189138	SCV000242770	pathogenic	not provided	2024-07-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect and suggest that this variant alters the channel activity of the SCN2A protein (PMID: 19786696, 37578743); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the transmembrane segment S1 of the third homologous domain; This variant is associated with the following publications: (PMID: 19786696, 28379373, 29655203, 32090326, 33057194, 25459969, 32651551, 35431799, 36084525, 37329172, 35982159, 31440721, 37578743, 34489640)
Genetic Services Laboratory, University of Chicago	RCV000118248	SCV000152615	pathogenic	Seizures, benign familial infantile, 3	2013-05-15	criteria provided, single submitter	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV002319425	SCV002605503	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only
Neurology Department, Shenzhen Children's Hospital	RCV001847619	SCV002099512	pathogenic	West syndrome	2022-02-16	no assertion criteria provided	clinical testing
OMIM	RCV000022767	SCV000044056	pathogenic	Developmental and epileptic encephalopathy, 11	2009-09-29	no assertion criteria provided	literature only

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