2-166038129-G-A

Position:

• chr2-166038129-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.2593C>T​(p.Arg865Ter) 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. R865R) has been classified as Likely 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:8
• Conservation: PhyloP100: 4.11

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 2-166038129-G-A is Pathogenic according to our data. Variant chr2-166038129-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166038129-G-A is described in Lovd as [Pathogenic]. Variant chr2-166038129-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.2593C>T	p.Arg865Ter	stop_gained	18/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.2593C>T	p.Arg865Ter	stop_gained	18/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+1999G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 152038 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Center of Excellence for Medical Genomics, Chulalongkorn University	Oct 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A heterozygous nonsense variation in exon 18 of the SCN1A gene (c.2593C>T) that results in a stop codon and premature truncation of the protein at codon 865 (p.Arg865Ter) was detected. The observed variant is not reported in gnomAD database and 1000 genome database. The reference base is conserved across the species and in-silico predictions by CADD and Mutation taster are damaging. This variant is a stop gained variant which occurs in an exon of SCN1A upstream of where nonsense mediated decay is predicted to occur. There are 239 downstream pathogenic loss of function variants, with the furthest variant being 1061 residues downstream of this variant. This indicates that the region is critical to protein function. The gene SCN1A has a low rate of benign loss of function variants as indicated by a low upper bound of the observed/expected confidence interval 0.07. The p.Arg865Ter 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 452 others. The variant p.Arg865Ter has been previously classified as Pathogenic in ClinVar (Variation ID 189844 as of 2021-04-01) with respect to Severe myoclonic epilepsy in infancy and 2 other conditions with a status of (2 stars) criteria provided, multiple submitters, no conflicts. Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 19, 2020	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change creates a premature translational stop signal (p.Arg865*) 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, severe myoclonic epilepsy in infancy, and intractable epilepsy (PMID: 12083760, 18076640, 18930999, 21868258, 23195492). This variant is also known as C2560T (R854X). ClinVar contains an entry for this variant (Variation ID: 189844). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2015

The R865X nonsense variant in the SCN1A gene has been reported previously in association with intractableepilepsy and Dravet syndrome (Wang et al., 2012; Lim et al., 2011; SCN1A Variant Database). It was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. This variant ispredicted to cause loss of normal protein function either through protein truncation or nonsense-mediatedmRNA decay. Therefore, the R865X variant is considered pathogenic. -

SCN1A-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2024

The SCN1A c.2593C>T variant is predicted to result in premature protein termination (p.Arg865*). In the literature, this variant is also referred to as C2560T or R837X using alternative transcripts. This variant has been reported in individuals with Dravet syndrome and other epilepsy phenotypes (see, for example, Ohmori et al. 2002. PubMed ID: 12083760; Lim et al. 2011. PubMed ID: 21868258; E-Table A, Wang et al. 2012. PubMed ID: 23195492; Zhou et al. 2018. PubMed ID: 29314583). It occurred de novo in multiple individuals (Ohmori et al. 2002. PubMed ID: 12083760; Zhou et al. 2018. PubMed ID: 29314583; Wang et al. 2021. PubMed ID: 33278787) and in one family, an unaffected parent was found to be mosaic for this variant (Xu et al. 2015. PubMed ID: 26096185). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in SCN1A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Dec 01, 2021

de novo truncating variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.91, 0.91, 0.92, 0.93
GERP RS		4.9

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: rs794726697; hg19: chr2-166894639; COSMIC: COSV57676304; COSMIC: COSV57676304;