ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.2995G>A (p.Glu999Lys)

dbSNP: rs796053126
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189130 SCV000242762 pathogenic not provided 2017-07-25 criteria provided, single submitter clinical testing The E999K variant has been reported previously as a de novo variant in multiple individuals with Ohtahara syndrome, early infantile epileptic encephaopathy, and severe intellectual disability (Nakamura et al., 2013, Allen et al., 2015, Trump et al., 2016). The E999K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E999K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a conserved position in the intracellular loop between the second and third transmembrane domains (Shi et al., 2012), and other missense variants have been reported in this region of the protein in association with epilepsy. A missense change at the same codon (E999V) has been reported in association with SCN2A-related disorder (Stenson et al., 2014, Trump et al., 2016). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, E999K is considered a pathogenic variant.
NeuroMeGen, Hospital Clinico Santiago de Compostela RCV000496128 SCV000586737 likely pathogenic Developmental and epileptic encephalopathy, 11 criteria provided, single submitter clinical testing
Invitae RCV000814425 SCV000954835 pathogenic Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 2023-06-27 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 206981). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 23935176, 26648591, 26993267, 27867041, 28379373). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 999 of the SCN2A protein (p.Glu999Lys). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000496128 SCV001520569 pathogenic Developmental and epileptic encephalopathy, 11 2020-02-06 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GenomeConnect - Simons Searchlight RCV001265328 SCV001443445 pathogenic Complex neurodevelopmental disorder 2016-07-14 no assertion criteria provided provider interpretation Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-07-14 and interpreted as Pathogenic. Variant was initially reported on 2015-07-31 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.
Neurology Department, Shenzhen Children's Hospital RCV001847839 SCV002099460 pathogenic West syndrome 2022-02-16 no assertion criteria provided clinical testing
Neurology Department, Shenzhen Children's Hospital RCV001847840 SCV002099501 pathogenic Epilepsy of infancy with migrating focal seizures 2022-02-16 no assertion criteria provided clinical testing
Department of Neurology, Children’s Hospital of Chongqing Medical University RCV003155928 SCV002577346 pathogenic Developmental and epileptic encephalopathy, 30 no assertion criteria provided research
Channelopathy-Associated Epilepsy Research Center RCV001265328 SCV002605500 not provided Complex neurodevelopmental disorder no assertion provided literature only

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