ClinVar Miner

Submissions for variant NM_001165963.2(SCN1A):c.4171A>C (p.Asn1391His) (rs1295072436)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000716093 SCV000846926 uncertain significance History of neurodevelopmental disorder 2016-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000520201 SCV000617957 likely pathogenic not provided 2017-11-02 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the SCN1A gene. The N1391H variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different missense variant at the same position (N1391S) was previously identified in a patient with Dravet syndrome; however paternal testing was not performed (Depienne et al., 2009). The N1391H variant is not observed at a significant frequency in large population cohorts (Lek et al.,2016). The N1391H variant is a semi-conservative amino acid substitution, which may impactsecondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and is predicted to be within the extracellular loop between theS5 and S6 transmembrane segments of the third homologous domain of the SCN1A protein. Multiple missense variants in nearby residues 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. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. Therefore, this variant is likely pathogenic; however, the possibility that it isbenign cannot be excluded.
Invitae RCV000636270 SCV000757709 uncertain significance Early infantile epileptic encephalopathy 2017-11-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 1391 of the SCN1A protein (p.Asn1391His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN1A-related disease. This variant identified in the SCN1A gene is located in the transmembrane spanning DIII-S5/S6 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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