2-166054637-C-T

Variant names:

• chr2-166054637-C-T
• rs794726827
• NM_001165963.4:c.602+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.602+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 U:1
• Conservation: PhyloP100: 7.90
• Publications: 15 publications found

Genes affected

SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.021393035 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-166054637-C-T is Pathogenic according to our data. Variant chr2-166054637-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 197187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.602+1G>A		splice_donor_variant, intron_variant	Intron 7 of 28	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.602+1G>A		splice_donor_variant, intron_variant	Intron 7 of 28		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.602+1G>A		splice_donor_variant, intron_variant	Intron 6 of 27	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.602+1G>A		splice_donor_variant, intron_variant	Intron 4 of 25	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.602+1G>A		splice_donor_variant, intron_variant	Intron 6 of 27	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

May 01, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN1A: PVS1, PM2 -

Dec 26, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 15, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe myoclonic epilepsy in infancy Pathogenic:3 Uncertain:1

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Dec 18, 2017

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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. -

Aug 07, 2017

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2021

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:3

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2023

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2018

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3;C5543353:Developmental and epileptic encephalopathy 6B Pathogenic:2

Dec 08, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1_Strong+PS4+PS2 -

Migraine, familial hemiplegic, 3 Pathogenic:1

Sep 08, 2002

Center of Excellence for Medical Genomics, Chulalongkorn University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Developmental and epileptic encephalopathy Pathogenic:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Dravet syndrome or Lennox-Gastout syndrome (PMID: 12566275, 20522430, 23934111, 28148630). In at least one individual the variant was observed to be de novo. This variant is also known as exon 4 splice site GT>AT, and 2:166911147 C/T. 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. For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy, 76 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

See cases Pathogenic:1

Aug 16, 2024

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PS4,PM2 -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3 Pathogenic:1

Jul 03, 2018

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Focal impaired awareness seizure Pathogenic:1

Nov 01, 2020

Pediatrics, MediClubGeorgia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Seizure Pathogenic:1

Apr 25, 2025

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autism;C0036572:Seizure;C0557874:Global developmental delay Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794726827; hg19: chr2-166911147; COSMIC: COSV57662425;