NM_001165963.4(SCN1A):c.3925C>G (p.Leu1309Val) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 23, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000821070.7

Allele description [Variation Report for NM_001165963.4(SCN1A):c.3925C>G (p.Leu1309Val)]

NM_001165963.4(SCN1A):c.3925C>G (p.Leu1309Val)

Genes:

SCN1A:sodium voltage-gated channel alpha subunit 1 [Gene - OMIM - HGNC]
LOC102724058:uncharacterized LOC102724058 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

2q24.3

Genomic location:

Preferred name:

NM_001165963.4(SCN1A):c.3925C>G (p.Leu1309Val)

HGVS:

NC_000002.12:g.166009796G>C
NG_011906.1:g.68844C>G
NM_001165963.4:c.3925C>GMANE SELECT
NM_001165963.4:c.3925C>G
NM_001165964.3:c.3841C>G
NM_001202435.3:c.3925C>G
NM_001353948.2:c.3925C>G
NM_001353949.2:c.3892C>G
NM_001353950.2:c.3892C>G
NM_001353951.2:c.3892C>G
NM_001353952.2:c.3892C>G
NM_001353954.2:c.3889C>G
NM_001353955.2:c.3889C>G
NM_001353957.2:c.3841C>G
NM_001353958.2:c.3841C>G
NM_001353960.2:c.3838C>G
NM_001353961.2:c.1483C>G
NM_006920.6:c.3892C>G
NP_001159435.1:p.Leu1309Val
NP_001159436.1:p.Leu1281Val
NP_001189364.1:p.Leu1309Val
NP_001340877.1:p.Leu1309Val
NP_001340878.1:p.Leu1298Val
NP_001340879.1:p.Leu1298Val
NP_001340880.1:p.Leu1298Val
NP_001340881.1:p.Leu1298Val
NP_001340883.1:p.Leu1297Val
NP_001340884.1:p.Leu1297Val
NP_001340886.1:p.Leu1281Val
NP_001340887.1:p.Leu1281Val
NP_001340889.1:p.Leu1280Val
NP_001340890.1:p.Leu495Val
NP_008851.3:p.Leu1298Val
LRG_8:g.68844C>G
NC_000002.11:g.166866306G>C
NC_000002.11:g.166866306G>C
NM_001165963.1:c.3925C>G
NR_148667.2:n.4278C>G

Protein change:

L1280V

Links:

dbSNP: rs121918801

NCBI 1000 Genomes Browser:

rs121918801

Molecular consequence:

NM_001165963.4:c.3925C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.3841C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.3925C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.3925C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.3892C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.3892C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.3892C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.3892C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.3889C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.3889C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.3841C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.3841C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.3838C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.1483C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.3892C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.4278C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Early infantile epileptic encephalopathy with suppression bursts (EIEE)
Synonyms:: Early infantile epileptic encephalopathy; Ohtahara syndrome; Developmental and epileptic encephalopathy
Identifiers:: MONDO: MONDO:0100062; MedGen: C0393706; Orphanet: 1934; OMIM: PS308350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000961811	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 23, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20117752, 28102150, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000961811

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 23, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Generalized epilepsy with febrile seizures plus: novel SCN1A mutation.

Dimova PS, Yordanova I, Bojinova V, Jordanova A, Kremenski I.

Pediatr Neurol. 2010 Feb;42(2):137-40. doi: 10.1016/j.pediatrneurol.2009.09.007.

PubMed [citation]

PMID:: 20117752

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study.

Epi4K consortium.; Epilepsy Phenome/Genome Project..

Lancet Neurol. 2017 Feb;16(2):135-143. doi: 10.1016/S1474-4422(16)30359-3.

PubMed [citation]

PMID:: 28102150

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000961811.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant has been observed to segregate with epilepsy in a family (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu1309 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20117752, 28102150). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 1309 of the SCN1A protein (p.Leu1309Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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