ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4129G>A (p.Glu1377Lys) (rs775820803)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188943 SCV000242574 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing The E1388K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E1388K variant is observed in 4/245324 (0.002%) alleles in large population cohorts (Lek et al., 2016). The E1388K 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 is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the third homologous domain. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with SCN1A-related disorder (Stenson et al., 2014). However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000814902 SCV000955339 uncertain significance Early infantile epileptic encephalopathy 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1388 of the SCN1A protein (p.Glu1388Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs775820803, ExAC 0.003%). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 206820). 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 tolerated, 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.

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