ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4547C>A (p.Ser1516Ter)

dbSNP: rs139300715
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188961 SCV000242592 pathogenic not provided 2022-04-15 criteria provided, single submitter clinical testing Reported as a de novo variant in association with severe myoclonic epilepsy in infancy (SMEI) and Dravet syndrome (Sugawara et al., 2002; Mancardi et al., 2006; Harkin et al., 2007; Depienne et al., 2009; Doccini et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26544041, 17347258, 25525159, 24168886, 26169758, 11940708, 18930999, 28837158, 30525188, 17054684, 31864146, 32090326, 33108073)
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000416525 SCV000494451 pathogenic Severe myoclonic epilepsy in infancy 2016-07-06 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000188961 SCV000615037 pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000416525 SCV000807531 pathogenic Severe myoclonic epilepsy in infancy 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 10-month-old female with afebrile seizures (onset 4m), IUGR, neonatal jaundice and neaonatal hypothermia
Fulgent Genetics, Fulgent Genetics RCV000763458 SCV000894235 pathogenic Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001050764 SCV001214886 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2023-05-19 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 206837). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 11940708, 19589774, 26544041). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1516*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999).
Blueprint Genetics RCV000416525 SCV001426156 pathogenic Severe myoclonic epilepsy in infancy 2018-03-23 criteria provided, single submitter clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV003448284 SCV004176500 pathogenic Generalized epilepsy with febrile seizures plus, type 2 2023-02-14 criteria provided, single submitter clinical testing The stop gained c.4547C>A(p.Ser1516Ter) variant in SCN1A gene has been reported previously in heterozygous state in multiple patients affected with epilepsy (Zhang Y, et. al., 2015). The c.4547C>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Pathogenic (multiple submission). The nucleotide change c.4547C>A in SCN1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000188961 SCV001929587 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000188961 SCV001958735 pathogenic not provided no assertion criteria provided clinical testing

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