ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4991T>C (p.Met1664Thr) (rs121918765)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460126 SCV000548766 likely pathogenic Early infantile epileptic encephalopathy 2017-05-23 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1664 of the SCN1A protein (p.Met1664Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an SCN1A-related disease. Family studies have indicated that this variant was not present in the parents of an individual with neonatal seizures, which suggests that it was de novo in that affected individual (Invitae). This variant is located in an extracellular D4 cytoplasmic domain, a region of the SCN1A protein where several previously reported SCN1A missense mutations are found (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. In summary, this variant is a novel missense change that has been shown to arise de novo in an affected individual. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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