ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.5587C>T (p.Arg1863Trp) (rs796053043)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189011 SCV000242642 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN1A gene. The R1874W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1874W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1874W 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 located within the C-terminal cytoplasmic domain of the SCN1A protein, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014). Based on the currently available information, it is unclear whether the R1874W variant is a pathogenic variant or a rare benign variant.
Invitae RCV000697361 SCV000825965 uncertain significance Early infantile epileptic encephalopathy 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1874 of the SCN1A protein (p.Arg1874Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of early infantile epileptic encephalopathy and their mother, who had arrthythmia during pregnancy (Invitae). ClinVar contains an entry for this variant (Variation ID: 206873). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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