GeneBe

rs727504136

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.3733C>T​(p.Arg1245*) variant causes a stop gained change involving the alteration of a non-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

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.19

Publications

12 publications found
Variant links:
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)

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 2-166012255-G-A is Pathogenic according to our data. Variant chr2-166012255-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 167639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN1ANM_001165963.4 linkc.3733C>T p.Arg1245* stop_gained Exon 22 of 29 ENST00000674923.1 NP_001159435.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN1AENST00000674923.1 linkc.3733C>T p.Arg1245* stop_gained Exon 22 of 29 NM_001165963.4 ENSP00000501589.1
SCN1AENST00000303395.9 linkc.3733C>T p.Arg1245* stop_gained Exon 21 of 28 5 ENSP00000303540.4
SCN1AENST00000375405.7 linkc.3700C>T p.Arg1234* stop_gained Exon 19 of 26 5 ENSP00000364554.3
SCN1AENST00000409050.2 linkc.3649C>T p.Arg1217* stop_gained Exon 21 of 28 5 ENSP00000386312.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00000473
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Apr 26, 2019
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17054684, 21906962, 24168886, 25525159, 12821740, 22150645, 26096185, 31009440, 30945278, 31864146, 32090326, 31031587) -

Feb 20, 2014
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Severe myoclonic epilepsy in infancy Pathogenic:2
Dec 20, 2014
Center for Bioinformatics, Peking University
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Feb 13, 2015
Athena Diagnostics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Pathogenic:1
Sep 15, 2016
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R1245* pathogenic mutation (also known as c.3733C>T), located in coding exon 19 of the SCN1A gene, results from a C to T substitution at nucleotide position 3733. This changes the amino acid from an arginine to a stop codon within coding exon 19. This alteration has been reported in individuals with severe myoclonic epilepsy of infancy (SMEI) and Dravet syndrome. (Craig AK et al. Seizure, 2012 Jan;21:17-20; Nabbout R et al. Neurology, 2003 Jun;60:1961-7; Zhang Y et al. PLoS ONE, 2015 Nov;10:e0141782). 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. -

Developmental and epileptic encephalopathy Pathogenic:1
Dec 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg1245*) 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 early infantile epileptic encephalopathy (PMID: 12821740). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 167639). For these reasons, this variant has been classified as Pathogenic. -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3;C5543353:Developmental and epileptic encephalopathy 6B Pathogenic:1
May 20, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Seizure Pathogenic:1
Jul 23, 2024
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
39
DANN
Uncertain
1.0
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.83
D
PhyloP100
2.2
Vest4
0.99, 0.98, 0.98
GERP RS
2.7
Mutation Taster
=0/200
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727504136; hg19: chr2-166868765; COSMIC: COSV57685915; COSMIC: COSV57685915; API