ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.1702C>T (p.Arg568Ter) (rs886039430)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254726 SCV000321925 pathogenic not provided 2016-10-21 criteria provided, single submitter clinical testing The R568X nonsense variant in the SCN1A gene has been reported multiple times previously in association withSCN1A-related disorders (Ohmori et al., 2002; SCN1A Variant Database). Functional studies suggest that the R568Xvariant results in a nonfunctional Nav1.1 protein (Ohmori et al., 2008). This pathogenic variant is predicted to causeloss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768077 SCV000898949 pathogenic Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2017-12-04 criteria provided, single submitter clinical testing SCN1A: NM_01165963.1 exon11 p.Arg568* (c.1702C>T): This variant has been reported in the literature in at least 1 individual with Dravet syndrome, as a de novo variant (Ohmori 2002, PMID:12083760, Ohmori 2008 PMID:18755274, Okumura 2012, PMID:22092154). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID: 265254). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies for this variant are unclear (Ohmori 2008, PMID18755274). However, this variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic based on presence of this variant as de novo in an affected individual, absence from controls and predicted impact to the protein.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000254726 SCV001249699 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198880 SCV001369875 pathogenic Familial hemiplegic migraine type 3 2018-09-28 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4,PM2,PM4.
Invitae RCV001382872 SCV001581826 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-09-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg568*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Dravet syndrome (PMID: 12083760, 29852413). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265254). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV001194613 SCV001364267 pathogenic Severe myoclonic epilepsy in infancy 2020-02-19 no assertion criteria provided clinical testing

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