rs794726710

chr2-166013812-G-Achr2-166013812-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001165963.4(SCN1A):c.3637C>T(p.Arg1213Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN1A NM_001165963.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.76

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-166013812-G-A is Pathogenic according to our data. Variant chr2-166013812-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166013812-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.3637C>T	p.Arg1213Ter	stop_gained	21/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-1801G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.3637C>T	p.Arg1213Ter	stop_gained	21/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-1801G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460560 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 10, 2014	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 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: 25525159, 30368457, 32090326, 28005047, 29573403, 35571021, 31440721, 29186148, 26096185, 26232052, 35074891, 18930999, 15346159, 23934111, 12566275, 23195492) -

Migraine, familial hemiplegic, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center of Excellence for Medical Genomics, Chulalongkorn University

Sep 08, 2002

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2018

The p.R1213* pathogenic mutation (also known as c.3637C>T), located in coding exon 18 of the SCN1A gene, results from a C to T substitution at nucleotide position 3637. This changes the amino acid from an arginine to a stop codon within coding exon 18. This mutation has been detected in multiple patients with early onset epilepsy phenotypes including Dravet syndrome and intractable epilepsy in infancy, with some cases reported as occurring de novo (Fujiwara T et al. Brain. 2003;126:531-46; Depienne C et al. J. Med. Genet., 2009;46:183-91; Wang JW et al. Epilepsy Res. 2012;102:195-200; Allen et al. Nature. 2013;501:217-21; van Egmond ME et al. Eur. J. Paediatr. Neurol., 2015;19:726-9; Zhu X et al. PLoS Genet. 2017;13:e1007104). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 10, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189861). This premature translational stop signal has been observed in individual(s) with intractable epilepsy and Dravet syndrome (PMID: 12566275, 18930999, 23195492, 23934111). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1213*) 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). -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Sep 14, 2017

This pathogenic mutation in the SCN1A gene was found in a child with epilepsy since the age of 5 months. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	42
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.94, 0.96, 0.95, 0.96
GERP RS		4.5

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: rs794726710; hg19: chr2-166870322; COSMIC: COSV57680304; COSMIC: COSV57680304;