VCV000197187.49 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(18)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 197187 Accession: VCV000197187.49

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 166054637 (GRCh38) [ NCBI UCSC ] 2: 166911147 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 28, 2015	Oct 20, 2024	Sep 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001165963.4:c.602+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001165964.3:c.602+1G>A		splice donor
NM_001202435.3:c.602+1G>A		splice donor
NM_001353948.2:c.602+1G>A		splice donor
NM_001353949.2:c.602+1G>A		splice donor
NM_001353950.2:c.602+1G>A		splice donor
NM_001353951.2:c.602+1G>A		splice donor
NM_001353952.2:c.602+1G>A		splice donor
NM_001353954.2:c.602+1G>A		splice donor
NM_001353955.2:c.602+1G>A		splice donor
NM_001353957.2:c.602+1G>A		splice donor
NM_001353958.2:c.602+1G>A		splice donor
NM_001353960.2:c.602+1G>A		splice donor
NM_001353961.2:c.-1824+1G>A		splice donor
NM_006920.6:c.602+1G>A		splice donor
NC_000002.12:g.166054637C>T
NC_000002.11:g.166911147C>T
NG_011906.1:g.24003G>A
LRG_8:g.24003G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:166054636:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

loss_of_function_variant; Sequence Ontology [ SO:0002054]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA302978 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SCN1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2245	4634

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Severe myoclonic epilepsy in infancy	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000178154.9
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000188832.35
Generalized epilepsy with febrile seizures plus, type 2 Migraine, familial hemiplegic, 3 Severe myoclonic epilepsy in infancy	Pathogenic (1)	criteria provided, single submitter	Jul 3, 2018	RCV000768306.3
Autism Global developmental delay Seizure	Pathogenic (1)	no assertion criteria provided	-	RCV001003957.3
Generalized epilepsy with febrile seizures plus, type 2	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 18, 2023	RCV001004746.9
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Apr 22, 2023	RCV001227678.8
Focal impaired awareness seizure	Pathogenic (1)	criteria provided, single submitter	Nov 1, 2020	RCV001290257.3
Migraine, familial hemiplegic, 3	Pathogenic (1)	no assertion criteria provided	Sep 8, 2002	RCV002281567.2
Developmental and epileptic encephalopathy, 76	Pathogenic (1)	criteria provided, single submitter	-	RCV003338449.2
Developmental and epileptic encephalopathy 6B Generalized epilepsy with febrile seizures plus, type 2 Migraine, familial hemiplegic, 3 Severe myoclonic epilepsy in infancy	Pathogenic (1)	criteria provided, single submitter	Dec 8, 2021	RCV003224195.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 01, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230159.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 12566275‚ 22071555‚ 22409937 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN1A Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Jul 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Generalized epilepsy with febrile seizures plus, type 2 Severe myoclonic epilepsy in infancy Generalized epilepsy with febrile seizures plus, type 2 Migraine, familial hemiplegic, 3 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV000898951.1 First in ClinVar: Apr 25, 2019 Last updated: Apr 25, 2019	Comment: 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 … (more) 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. (less)
Pathogenic (Nov 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Focal impaired awareness seizure (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Pediatrics, MediClubGeorgia Accession: SCV001478082.1 First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021	Publications: PubMed (3) PubMed: 16199547‚ 17347258‚ 12566275 Comment: 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 … (more) 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. (less) Clinical Features: EEG abnormality (present) , Seizure (present) , Focal impaired awareness seizure (present) Age: 0-9 years Sex: female Ethnicity/Population group: Caucasian Geographic origin: Georgia Testing laboratory: 500031 Date variant was reported to submitter: 2020-08-06 Testing laboratory interpretation: Pathogenic
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe myoclonic epilepsy in infancy Affected status: yes Allele origin: germline	3billion Accession: SCV002572535.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: 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 … (more) 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. (less) Clinical Features: Global developmental delay (present) , Atonic seizure (present)
Pathogenic (Dec 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy 6B Migraine, familial hemiplegic, 3 Severe myoclonic epilepsy in infancy Generalized epilepsy with febrile seizures plus, type 2 Generalized epilepsy with febrile seizures plus, type 2 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920419.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 76 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004046987.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Global developmental delay (present) , Hyperkinetic movements (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Generalized epilepsy with febrile seizures plus, type 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004171830.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
Pathogenic (Mar 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020005.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Apr 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Early infantile epileptic encephalopathy with suppression bursts Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001400047.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 12566275‚ 20522430‚ 23934111‚ 28148630‚ 16199547‚ 17347258‚ 18930999 Comment: 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 … (more) 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). (less)
Pathogenic (Dec 26, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242462.11 First in ClinVar: Aug 07, 2015 Last updated: Apr 17, 2019	Comment: 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 … (more) 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. (less)
Pathogenic (Aug 07, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe myoclonic epilepsy in infancy (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001164146.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (1) PubMed: 12566275
Pathogenic (Jul 20, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Generalized epilepsy with febrile seizures plus, type 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001164224.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Pathogenic (Apr 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe myoclonic epilepsy in infancy (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Centre for Inherited Metabolic Diseases, Karolinska University Hospital Accession: SCV001572548.1 First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021	Family history: no Sex: female Secondary finding: no
Pathogenic (Sep 18, 2023)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Generalized epilepsy with febrile seizures plus, type 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV004045843.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Publications: PubMed (1) PubMed: 29190809 Number of individuals with the variant: 1 Clinical Features: Bilateral tonic-clonic seizure (present) , Febrile seizure (within the age range of 3 months to 6 years) (present) , Focal-onset seizure (present)
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249707.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: SCN1A: PVS1, PM2 Number of individuals with the variant: 3
Pathogenic (-)	no assertion criteria provided Method: research	Autism Seizure Global developmental delay Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001161948.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 1
Uncertain significance (Dec 18, 2017)	no assertion criteria provided Method: clinical testing	Severe myoclonic epilepsy in infancy (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV000678272.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	Comment: 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 … (more) 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. (less) Clinical Features: Developmental regression (present) , Mental deterioration (present) , Aggressive behavior (present) , Oval face (present) , Low posterior hairline (present) , Delayed speech and language … (more) Developmental regression (present) , Mental deterioration (present) , Aggressive behavior (present) , Oval face (present) , Low posterior hairline (present) , Delayed speech and language development (present) , Seizure (present) (less) Age: 10-19 years Sex: female Ethnicity/Population group: Gujarati Hindu Geographic origin: India Method: The exon-intron boundaries of the SCN1A gene were bi-directionally sequenced using an automated sequencer.
Pathogenic (Sep 08, 2002)	no assertion criteria provided Method: research	Migraine, familial hemiplegic, 3 Affected status: yes Allele origin: unknown	Center of Excellence for Medical Genomics, Chulalongkorn University Accession: SCV002570038.1 First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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).

Comment:

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.

Comment:

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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)			Pediatrics, MediClubGeorgia Accession: SCV001478082.1	Publications PubMed (3)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes.	Ortega-Moreno L	PloS one	2017	PMID: 29190809
Dysarthria and broader motor speech deficits in Dravet syndrome.	Turner SJ	Neurology	2017	PMID: 28148630
De novo mutations in epileptic encephalopathies.	Epi4K Consortium	Nature	2013	PMID: 23934111
Progressive gait deterioration in adolescents with Dravet syndrome.	Rodda JM	Archives of neurology	2012	PMID: 22409937
Early clinical features in Dravet syndrome patients with and without SCN1A mutations.	Petrelli C	Epilepsy research	2012	PMID: 22071555
Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome.	Depienne C	Journal of medical genetics	2010	PMID: 20522430
Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients.	Depienne C	Journal of medical genetics	2009	PMID: 18930999
The spectrum of SCN1A-related infantile epileptic encephalopathies.	Harkin LA	Brain : a journal of neurology	2007	PMID: 17347258
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures.	Fujiwara T	Brain : a journal of neurology	2003	PMID: 12566275
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN1A	-	-	-	-
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Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

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