ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5383G>A (p.Glu1795Lys) (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 Familial hemiplegic migraine type 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 uncertain significance Early infantile epileptic encephalopathy 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1795 of the SCN1A protein (p.Glu1795Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with generalized epilepsy with febrile seizures plus (GEFS+) in a family (PMID: 20600615). ClinVar contains an entry for this variant (Variation ID: 68660). This variant identified in the SCN1A gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. 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. 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.
UniProtKB/Swiss-Prot RCV000059540 SCV000091072 not provided Generalized epilepsy with febrile seizures plus, type 1 no assertion provided not provided

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