rs794726799

Variant names:

• chr2-166047668-G-A
• rs794726799
• NM_001165963.4:c.1129C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.1129C>T​(p.Arg377*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R377R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.99
• Publications: 5 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 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-166047668-G-A is Pathogenic according to our data. Variant chr2-166047668-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 189963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.1129C>T	p.Arg377*	stop_gained	Exon 11 of 29	NP_001159435.1
	SCN1A	NM_001353961.2		c.-1297C>T		5_prime_UTR_premature_start_codon_gain	Exon 10 of 28	NP_001340890.1
	SCN1A	NM_001202435.3		c.1129C>T	p.Arg377*	stop_gained	Exon 10 of 28	NP_001189364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.1129C>T	p.Arg377*	stop_gained	Exon 11 of 29	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.1129C>T	p.Arg377*	stop_gained	Exon 10 of 28	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.1129C>T	p.Arg377*	stop_gained	Exon 8 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 25525159, 17054684, 27465585, 30182498, 30321769, 26096185, 31009440, 30868114, 23808377, 30641252, 32090326, 33278787, 32427350, 31440721, 31031587, 28664031, 35074891, 36480001, 36801247)

Severe myoclonic epilepsy in infancy Pathogenic:3

Dec 20, 2014

Center for Bioinformatics, Peking University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop gained variant c.1129C>T(p.Arg377Ter) in SCN1A gene has been reported previously in individuals affected with Dravet syndrome (Djémié et al., 2016). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg377Ter variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The nucleotide change 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 in SCN1A are known to be pathogenic (Harkin et al., 2007; Depienne et al., 2009). For these reasons, this variant has been classified as Pathogenic.

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Developmental and epileptic encephalopathy Pathogenic:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg377*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 17054684, 23808377, 27465585). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189963). 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.

SCN1A-related disorder Pathogenic:1

Nov 12, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic 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: VCV000189963 /PMID: 17054684 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Seizure Pathogenic:1

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		5.0
Vest4		0.85
GERP RS		3.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: -41

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

Other links and lift over

dbSNP: rs794726799; hg19: chr2-166904178; COSMIC: COSV57667265;