rs398123593

chr2-166002537-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.4219C>T(p.Arg1407Ter) 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:6
• Conservation: PhyloP100: 4.01

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)

LOC102724058 (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 2-166002537-G-A is Pathogenic according to our data. Variant chr2-166002537-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 93649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.4219C>T	p.Arg1407Ter	stop_gained	24/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-13076G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.4219C>T	p.Arg1407Ter	stop_gained	24/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-13076G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SCN1A: PVS1, PM2, PM6 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	Not observed in large population cohorts (Lek et al., 2016); 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; This variant is associated with the following publications: (PMID: 17537961, 24155976, 25525159, 20831750, 24152123, 29329111, 29915537, 29141279, 25855492, 26749013, 25042160, 24502503, 15880351, 11940708, 16713920, 16458823, 30368457, 30868114, 31864146, 31765958) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2013	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2016

The p.R1407* pathogenic mutation (also known as c.4219C>T and p.R1396*), located in coding exon 21 of the SCN1A gene, results from a C to T substitution at nucleotide position 4219. This changes the amino acid from an arginine to a stop codon within coding exon 21. This mutation was reported as a de novo mutation in a male proband with severe myoclonic epilepsy in infancy, whose convulsions were often induced by fever or hot bath and were prone to occur in status epilepticus or in cluster (Sugawara T, et al. Neurology 2002; 58(7):1122-4). In addition, this mutation has been introduced into mice in two separate studies with similar outcomes, which include epileptic recurrent seizures, neuronal excitability, and cardiac electrophysiological abnormalities (Ogiwara I, et al. J. Neurosci. 2007;27(22):5903-14; Auerbach DS, et al. PLoS ONE 2013;8(10):e77843). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 20, 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: 93649). This variant is also known as 4186C>T and Arg1396X. This premature translational stop signal has been observed in individual(s) with severe myoclonic epilepsy in infancy (PMID: 11940708, 24502503). 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.Arg1407*) 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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Lifecell International Pvt. Ltd

-

A heterozygous nonsense variation in exon 24 of the SCN1A gene (c.4219C>T) that results in a stop codon and premature truncation of the protein at codon 1407 (p.Arg1407Ter) was detected. The observed variant is not reported in 1000 genome database and gnomAD database. The reference base is conserved across the species and in-silico predictions by CADD and Mutation taster are damaging. This variant is predicted to cause loss of normal protein function through protein truncation. The gene SCN1A has a low rate of benign loss of function variants as indicated by a high LoF variants Z-Score of 7.90. The p.R1407Ter variant is a loss of function variant in the gene SCN1A, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_001159435.1:p.M1I and 449 others. There are 112 downstream pathogenic loss of function variants, with the furthest variant being 519 residues downstream of the variant p.R1407Ter. This variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 93649 as of 2021-02-04). Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	41
Dann	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.99, 0.99, 0.99
GERP RS		4.7

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: rs398123593; hg19: chr2-166859047;