ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.677C>T (p.Thr226Met) (rs121917984)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188843 SCV000242473 pathogenic not provided 2019-05-03 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Berecki et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 17347258, 23895530, 21719429, 19585586, 18804930, 25401298, 28794249, 25741868, 30779207, 31257984, 31791873, 31864146, 31130284, 32581362, 33084218)
Invitae RCV000558296 SCV000633879 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2018-05-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 226 of the SCN1A protein (p.Thr226Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with Dravet syndrome and cryptogenic generalized epilepsy (PMID: 17347258, 23895530, 25401298). ClinVar contains an entry for this variant (Variation ID: 68578). This variant identified in the SCN1A gene is located in the transmembrane D1-S4 region of the resulting protein (PMID: 25348405, 18804930). 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. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763460 SCV000894237 pathogenic Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000059454 SCV001335359 pathogenic Severe myoclonic epilepsy in infancy 2018-01-01 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
UniProtKB/Swiss-Prot RCV000059454 SCV000090979 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003956 SCV001161947 pathogenic Global developmental delay; Seizures no assertion criteria provided research
OMIM RCV001420531 SCV001622834 pathogenic Developmental and epileptic encephalopathy 6B 2007-03-01 no assertion criteria provided literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000188843 SCV001798268 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000188843 SCV001930492 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000188843 SCV001956265 pathogenic not provided no assertion criteria provided clinical testing

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