NM_001165963.4(SCN1A):c.3776T>C (p.Phe1259Ser) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 12, 2024
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:: RCV000701047.15

Allele description [Variation Report for NM_001165963.4(SCN1A):c.3776T>C (p.Phe1259Ser)]

NM_001165963.4(SCN1A):c.3776T>C (p.Phe1259Ser)

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.3776T>C (p.Phe1259Ser)

Other names:

p.F1259S:TTC>TCC

HGVS:

NC_000002.12:g.166012212A>G
NG_011906.1:g.66428T>C
NM_001165963.4:c.3776T>CMANE SELECT
NM_001165963.4:c.3776T>C
NM_001165964.3:c.3692T>C
NM_001202435.3:c.3776T>C
NM_001353948.2:c.3776T>C
NM_001353949.2:c.3743T>C
NM_001353950.2:c.3743T>C
NM_001353951.2:c.3743T>C
NM_001353952.2:c.3743T>C
NM_001353954.2:c.3740T>C
NM_001353955.2:c.3740T>C
NM_001353957.2:c.3692T>C
NM_001353958.2:c.3692T>C
NM_001353960.2:c.3689T>C
NM_001353961.2:c.1334T>C
NM_006920.6:c.3743T>C
NP_001159435.1:p.Phe1259Ser
NP_001159436.1:p.Phe1231Ser
NP_001189364.1:p.Phe1259Ser
NP_001340877.1:p.Phe1259Ser
NP_001340878.1:p.Phe1248Ser
NP_001340879.1:p.Phe1248Ser
NP_001340880.1:p.Phe1248Ser
NP_001340881.1:p.Phe1248Ser
NP_001340883.1:p.Phe1247Ser
NP_001340884.1:p.Phe1247Ser
NP_001340886.1:p.Phe1231Ser
NP_001340887.1:p.Phe1231Ser
NP_001340889.1:p.Phe1230Ser
NP_001340890.1:p.Phe445Ser
NP_008851.3:p.Phe1248Ser
LRG_8:g.66428T>C
NC_000002.11:g.166868722A>G
NC_000002.11:g.166868722A>G
NM_001165963.1:c.3776T>C
NR_148667.2:n.4129T>C

Protein change:

F1230S

Links:

dbSNP: rs398123591

NCBI 1000 Genomes Browser:

rs398123591

Molecular consequence:

NM_001165963.4:c.3776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.3692T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.3776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.3776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.3743T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.3743T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.3743T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.3743T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.3740T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.3740T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.3692T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.3692T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.3689T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.1334T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.3743T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.4129T>C - 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
SCV000829829	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29655203, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000829829

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 12, 2024)

germline

clinical testing

PubMed (2)
[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

Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.

Lindy AS, Stosser MB, Butler E, Downtain-Pickersgill C, Shanmugham A, Retterer K, Brandt T, Richard G, McKnight DA.

Epilepsia. 2018 May;59(5):1062-1071. doi: 10.1111/epi.14074. Epub 2018 Apr 14.

PubMed [citation]

PMID:: 29655203

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000829829.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1259 of the SCN1A protein (p.Phe1259Ser). This variant is present in population databases (rs398123591, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of SCN1A-related conditions (PMID: 29655203; Invitae). ClinVar contains an entry for this variant (Variation ID: 93645). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

#	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: Apr 6, 2024

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