ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.2665G>A (p.Ala889Thr) (rs1266877537)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001696832 SCV000621064 likely pathogenic not provided 2020-06-22 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Substitution predicted to be within the transmembrane segment S5 of the second homologous domain; This variant is associated with the following publications: (PMID: 31487502, 30336400)
Invitae RCV000559503 SCV000633833 likely pathogenic Early infantile epileptic encephalopathy with suppression bursts 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 889 of the SCN1A protein (p.Ala889Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with SCN1A-related disease (Invitae database). 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. This variant identified in the SCN1A gene is located in the cytoplasmic D2-S4/S5 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253601 SCV001429410 likely pathogenic Severe myoclonic epilepsy in infancy 2019-02-04 criteria provided, single submitter clinical testing

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