ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.602+1G>A

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188832 SCV000230159 pathogenic not provided 2015-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000188832 SCV000242462 pathogenic not provided 2017-12-26 criteria provided, single submitter clinical testing The c.602+1 G>A splice site variant in the SCN1A gene has been reported previously multiple times as an assumed de novo or an inherited variant in association with Dravet syndrome and other SCN1A-related disorders (Fujiwara et al., 2003; Harkin et al., 2007; Depienne et al., 2009; SCN1A Variant Database). It has also been observed as an assumed de novo variant in individuals with epilepsy tested previously at GeneDx. The c.602+1 G>A pathogenic variant destroys the canonical splice donor site in intron 4, and is expected to cause abnormal gene splicing. It is not observed in large population cohorts (Lek et al., 2016). Therefore, the presence of c.602+1 G>A is consistent with the diagnosis of a SCN1A-related disorder in this individual.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768306 SCV000898951 pathogenic Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-07-03 criteria provided, single submitter clinical testing SCN1A NM_001165963.1 exon 4 c.602+1G>A: This variant has been reported in the literature in at least 8 individuals with Dravet syndrome/epileptic encephalopathy, segregating with disease in at least 2 affected family members and reported as de novo in at least 4 individuals (Marini 2006 PMID:17054697, Depienne 2010 PMID:20522430, Rodda 2012 PMID:22409937, Allen 2013 PMID:23934111, Ortega-Moreno 2017 PMID:29190809, Turner 2017 PMID:28148630). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:197187). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function has been reported as a disease mechanism for this gene and disease (Depienne 2009 PMID:18930999). In summary, this variant is classified as pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000178154 SCV001164146 pathogenic Severe myoclonic epilepsy in infancy 2017-08-07 criteria provided, single submitter clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001004746 SCV001164224 pathogenic Generalized epilepsy with febrile seizures plus, type 2 2018-07-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188832 SCV001249707 pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
Invitae RCV001227678 SCV001400047 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-09-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the SCN1A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Dravet syndrome in a family (PMID: 20522430) and was identified several individuals affected with SCN1A-related disease (PMID: 12566275, 28148630, 23934111). This variant is also known as exon 4 splice site GT>AT, and 2:166911147 C/T in the literature. ClinVar contains an entry for this variant (Variation ID: 197187). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). For these reasons, this variant has been classified as Pathogenic.
Pediatrics, MediClubGeorgia RCV001290257 SCV001478082 pathogenic Focal seizures with impairment of consciousness or awareness 2020-11-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the SCN1A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function. Unaffected mother is mosaic for this variant. This variant has been described in several affected individuals.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000178154 SCV001572548 pathogenic Severe myoclonic epilepsy in infancy 2021-04-25 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000178154 SCV000678272 uncertain significance Severe myoclonic epilepsy in infancy 2017-12-18 no assertion criteria provided clinical testing The observed variant c.602+1G>A (5' splice site) has not been reported in 1000 genomes and ExAC databases. However, it is reported in a publication by Djemie T et al. 2016. The in silico prediction of the variant is damaging by MutationTaster2.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003957 SCV001161948 pathogenic Autistic disorder of childhood onset; Global developmental delay; Seizures no assertion criteria provided research

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