ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5988A>C (p.Lys1996Asn) (rs371243629)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000593278 SCV000703160 uncertain significance not provided 2016-12-07 criteria provided, single submitter clinical testing
Invitae RCV000636263 SCV000757702 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2017-10-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1996 of the SCN1A protein (p.Lys1996Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. 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. 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.
Fulgent Genetics,Fulgent Genetics RCV000764281 SCV000895300 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
GeneDx RCV000593278 SCV001792583 uncertain significance not provided 2019-09-30 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the C-terminal cytoplasmic domain.

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