ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5383G>A (p.Glu1795Lys)

dbSNP: rs121918813
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489760 SCV000576513 uncertain significance not specified 2017-05-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN1A gene. The E1795K variant has been previously reported in multiple affected individuals in a family with generalized epilepsy with febrile seizures plus (GEFS+) (Li et al., 2010). The E1795K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E1795K 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 occurs at a conserved position predicted to be within the C-terminal cytoplasmic domain, and missense variants in this region have been reported in association with SCN1A-related disorders (SCN1A Variant Database; Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Fulgent Genetics,Fulgent Genetics RCV000764284 SCV000895303 uncertain significance Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000792317 SCV000931604 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2021-10-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, a(n) acidic and polar amino acid, with lysine, a(n) basic and polar amino acid, at codon 1795 of the SCN1A protein (p.Glu1795Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of generalized epilepsy with febrile seizures plus (GEFS+) (PMID: 20600615; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68660). 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 SCN1A protein function. For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot RCV000059540 SCV000091072 not provided Generalized epilepsy with febrile seizures plus, type 1 no assertion provided not provided

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