chr2-165996047-G-T

Position:

• chr2-165996047-G-T

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.4547C>A​(p.Ser1516*) variant causes a stop gained 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. 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:12
• Conservation: PhyloP100: 10.0

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 (HGNC:):

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 2-165996047-G-T is Pathogenic according to our data. Variant chr2-165996047-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 206837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996047-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4547C>A	p.Ser1516*	stop_gained	27/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4547C>A	p.Ser1516*	stop_gained	27/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4547C>A	p.Ser1516*	stop_gained	26/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4514C>A	p.Ser1505*	stop_gained	24/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4463C>A	p.Ser1488*	stop_gained	24/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2022	Reported as a de novo variant in association with severe myoclonic epilepsy in infancy (SMEI) and Dravet syndrome (Sugawara et al., 2002; Mancardi et al., 2006; Harkin et al., 2007; Depienne et al., 2009; Doccini et al., 2015); 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: 26544041, 17347258, 25525159, 24168886, 26169758, 11940708, 18930999, 28837158, 30525188, 17054684, 31864146, 32090326, 33108073) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Severe myoclonic epilepsy in infancy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 10-month-old female with afebrile seizures (onset 4m), IUGR, neonatal jaundice and neaonatal hypothermia -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN1A-related epilepsy (PMID: 28488083). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance has been noted to vary by phenotype (PMID: 20301494). (I) 0115 - Variants in this gene are known to have variable expressivity. Both intrafamilial and interfamilial variability has been observed (PMID: 20301494). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jul 06, 2016	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 19, 2023

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: 206837). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 11940708, 19589774, 26544041). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1516*) 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). -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Feb 14, 2023

The stop gained c.4547C>A(p.Ser1516Ter) variant in SCN1A gene has been reported previously in heterozygous state in multiple patients affected with epilepsy (Zhang Y, et. al., 2015). The c.4547C>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Pathogenic (multiple submission). The nucleotide change c.4547C>A 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. -

SCN1A-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

The SCN1A c.4547C>A variant is predicted to result in premature protein termination (p.Ser1516*). This variant, often described in the literature with alternate nomenclature (c.4514C>A; p.Ser150*), has been reported in several individuals with SCN1A-related epilepsy (See for example, Sugawara et al 2002. PubMed ID: 11940708; Zhang et al. 2015. PubMed ID: 26544041; Stawicka et al. 2024 PubMed ID: 38785537). In the vast majority of these patients, the variant was found to have occurred de novo in the patient (See for example, Mancardi et al. 2006. PubMed ID: 17054684; Heron et al. 2010. PubMed ID: 19589774; Supplementary Table 1-2, Essajee et al. 2022. PubMed ID: 36084525). However, the variant has been inherited from a mosaic parent by report (Stosser et al. 2017. PubMed ID: 28837158; eTable1, Moreno-De-Luca et al. 2021. PubMed ID: 33528536). Notably, one child with this variant was reported to respond well to Perampanel (Turón-Viñas E et al 2021. PubMed ID: 34692895). 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	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.97, 0.97, 0.97, 0.97
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: -34

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

Publications

LitVar

Other links and lift over

dbSNP: rs139300715; hg19: chr2-166852557;