rs794726730

chr2-166042334-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001165963.4(SCN1A):c.2134C>T(p.Arg712Ter) 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 (★★). 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:16
• Conservation: PhyloP100: 4.24

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

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 2-166042334-G-A is Pathogenic according to our data. Variant chr2-166042334-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166042334-G-A is described in Lovd as [Pathogenic]. Variant chr2-166042334-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.2134C>T	p.Arg712Ter	stop_gained	15/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.2134C>T	p.Arg712Ter	stop_gained	15/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+6204G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2023	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: 16458823, 22151702, 18930999, 32056211, 23195492, 23808377, 20522430, 25525159, 26096185, 26188943, 25754450, 19585586, 28079314, 28387369, 29100083, 30641252, 29933521, 11940708, 31864146, 32090326, 32139178, 34489640, 34163418, 34055682, 32651551, 31031587, 35074891, 35886038, 35253369, 35571373, 34992632) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2023	This variant has been identified in multiple unrelated individuals with Dravet syndrome and severe myoclonic epilepsy of infancy (SMEI) and has been confirmed to occur de novo in multiple individuals. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as R701X. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SCN1A: PS2:Very Strong, PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 17, 2022	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A heterozygous nonsense variation in exon 15 of the SCN1A gene (c.2134C>T) that results in a stop codon and premature truncation of the protein at codon 712 (p.Arg712Ter) was detected. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by CADD is damaging. The gene SCN1A has a low rate of benign loss of function variants as indicated by a high LoF variants Z-Score of 8.42. This variant is predicted to cause loss of normal protein function through protein truncation.This variant has previously been reported for early infantile epileptic encephalopathy by Arafat A et al., 2017. This variant was found in ClinVar (Variant 189886) with a classification of Pathogenic with respect to Early infantile epileptic encephalopathy with suppression bursts and a review status of (2 stars) no assertion criteria provided (https://www.ncbi.nlm.nih.gov/clinvar/variation/189886/). Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.2134C>T (p.Arg712Ter) stop gained variant in SCN1A gene has been reported previously in patients affected with Dravet syndrome in the de novo state (Wang et al., 2012), and in patients with epileptic encephalopathy (Ohimori et al., 2002). The p.Arg712Ter variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.2134C>T 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 have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Severe myoclonic epilepsy in infancy Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 03, 2023	Criteria applied: PVS1,PS4_MOD,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Autosomal dominant epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 14, 2022

Variant summary: SCN1A c.2134C>T (p.Arg712X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251266 control chromosomes. c.2134C>T has been reported in the literature in individuals with Dravet syndrome in the de novo state (eg. Wang_2012), and in patients with epileptic encephalopathy (eg Sugawara_2002, Ohimori_2002). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Developmental and epileptic encephalopathy, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2020

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2021

The c.2134C>T (p.R712*) alteration, located in exon 12 (coding exon 12) of the SCN1A gene, consists of a C to T substitution at nucleotide position 2134. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 712. Based on data from the Genome Aggregation Database (gnomAD), the SCN1A c.2134C>T alteration was not observed, with coverage at this position. This mutation has been detected in several individuals, in some cases as de novo occurrences, with Dravet syndrome, epileptic encephalopathy, severe intellectual disability, and non specific neurodevelopmental disorders (Gaily, 2013; Zhang, 2015; Do, 2017; Arafat, 2017; Hamdan, 2017; Froukh, 2020). The p.R712* alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189886). This premature translational stop signal has been observed in individual(s) with epileptic encephalopathy and Dravet syndrome (PMID: 11940708, 12083760, 18804930, 23195492, 23808377, 26544041). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg712*) 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). -

SCN1A-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

The SCN1A c.2134C>T variant is predicted to result in premature protein termination (p.Arg712*). This variant has been reported in many individuals with Dravet syndrome, and in several of these individuals, it occurred de novo (see, for example, Sugawara et al. 2002. PubMed ID: 11940708, reported as R701X; Table e-1, Zuberi et al. 2011. PubMed ID: 21248271; E-Table A, Wang et al. 2012. PubMed ID: 23195492). It has also been reported de novo in individuals with epileptic encephalopathy (Table S5, Hamdan et al. 2017. PubMed ID: 29100083; referred to as c.2050C>T, Sun et al. 2021. PubMed ID: 34055682). This variant has not been reported in a large population database, indicating it is rare. Nonsense variants in SCN1A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.99, 0.99, 0.99, 0.99
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs794726730; hg19: chr2-166898844; COSMIC: COSV57668399;