Submissions for variant NM_001165963.4(SCN1A):c.602+1G>A

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	Migraine, familial hemiplegic, 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 Center for Human Genetics Tuebingen	RCV000188832	SCV001249707	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	SCN1A: PVS1, PM2
Labcorp Genetics (formerly Invitae), Labcorp	RCV001227678	SCV001400047	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-04-22	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with Dravet syndrome and SCN1A-related disease (PMID: 12566275, 20522430, 23934111, 28148630). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the SCN1A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is also known as exon 4 splice site GT>AT, and 2:166911147 C/T. 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: 197187).
Pediatrics, MediClubGeorgia	RCV001290257	SCV001478082	pathogenic	Focal impaired awareness seizure	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
Revvity Omics, Revvity	RCV000188832	SCV002020005	pathogenic	not provided	2021-03-15	criteria provided, single submitter	clinical testing
3billion	RCV000178154	SCV002572535	pathogenic	Severe myoclonic epilepsy in infancy	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant on the canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000197187/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224195	SCV003920419	pathogenic	Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2; Developmental and epileptic encephalopathy 6B	2021-12-08	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001004746	SCV004045843	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2023-09-18	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338449	SCV004046987	pathogenic	Developmental and epileptic encephalopathy, 76		criteria provided, single submitter	clinical testing	The c.602+1 G>A splice site variant in the SCN1A gene has been reported previously in heterozygous state in several individuals affected with SCN1A-related disease (Fujiwara et al.,2003; Epi4K Consortium. et al., 2013) and observed to segregate with Dravet syndrome in a family (Depienne et al., 2009). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been submitted to ClinVar as Pathogenic. The nucleotide change in SCN1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle et al., 2005), and loss-of-function variants in SCN1A are known to be pathogenic (Harkin et al., 2007). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001004746	SCV004171830	pathogenic	Generalized epilepsy with febrile seizures plus, type 2		criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV003224195	SCV005417664	pathogenic	Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2; Developmental and epileptic encephalopathy 6B		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1_Strong+PS4+PS2
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	Autism; Global developmental delay; Seizure		no assertion criteria provided	research
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV002281567	SCV002570038	pathogenic	Migraine, familial hemiplegic, 3	2002-09-08	no assertion criteria provided	research