ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.3677T>C (p.Phe1226Ser) (rs1553531410)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520061 SCV000616953 uncertain significance not provided 2018-01-24 criteria provided, single submitter clinical testing The F1237S variant in the SCN1A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The F1237S variant was not observed in approximately 6500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The F1237S variant is a non-conservative amino acid substitution, which occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G1233R, A1236P, E1238D, D1239Y, D1239G) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret F1237S as a variant of uncertain significance.
Invitae RCV000706305 SCV000835347 uncertain significance Early infantile epileptic encephalopathy 2018-03-02 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 1237 of the SCN1A protein (p.Phe1237Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. 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. ClinVar contains an entry for this variant (Variation ID: 449140). This variant identified in the SCN1A gene is located in the transmembrane spanning D3-S1 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.

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