NM_001165963.4(SCN1A):c.4245T>A (p.Phe1415Leu) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 26, 2021
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:: RCV002942835.3

Allele description [Variation Report for NM_001165963.4(SCN1A):c.4245T>A (p.Phe1415Leu)]

NM_001165963.4(SCN1A):c.4245T>A (p.Phe1415Leu)

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.4245T>A (p.Phe1415Leu)

HGVS:

NC_000002.12:g.166002511A>T
NG_011906.1:g.76129T>A
NM_001165963.4:c.4245T>AMANE SELECT
NM_001165964.3:c.4161T>A
NM_001202435.3:c.4245T>A
NM_001353948.2:c.4245T>A
NM_001353949.2:c.4212T>A
NM_001353950.2:c.4212T>A
NM_001353951.2:c.4212T>A
NM_001353952.2:c.4212T>A
NM_001353954.2:c.4209T>A
NM_001353955.2:c.4209T>A
NM_001353957.2:c.4161T>A
NM_001353958.2:c.4161T>A
NM_001353960.2:c.4158T>A
NM_001353961.2:c.1803T>A
NM_006920.6:c.4212T>A
NP_001159435.1:p.Phe1415Leu
NP_001159436.1:p.Phe1387Leu
NP_001189364.1:p.Phe1415Leu
NP_001340877.1:p.Phe1415Leu
NP_001340878.1:p.Phe1404Leu
NP_001340879.1:p.Phe1404Leu
NP_001340880.1:p.Phe1404Leu
NP_001340881.1:p.Phe1404Leu
NP_001340883.1:p.Phe1403Leu
NP_001340884.1:p.Phe1403Leu
NP_001340886.1:p.Phe1387Leu
NP_001340887.1:p.Phe1387Leu
NP_001340889.1:p.Phe1386Leu
NP_001340890.1:p.Phe601Leu
NP_008851.3:p.Phe1404Leu
NP_008851.3:p.Phe1404Leu
LRG_8t1:c.4212T>A
LRG_8:g.76129T>A
LRG_8p1:p.Phe1404Leu
NC_000002.11:g.166859021A>T
NM_006920.4:c.4212T>A
NR_148667.2:n.4662T>A

Protein change:

F1386L

Molecular consequence:

NM_001165963.4:c.4245T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.4161T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.4245T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.4245T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.4212T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.4212T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.4212T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.4212T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.4209T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.4209T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.4161T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.4161T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.4158T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.1803T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.4212T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.4662T>A - 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
SCV003272020	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 26, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003272020

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 26, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003272020.2

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

Description

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.Phe1415 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1415 of the SCN1A protein (p.Phe1415Leu).

#	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: Sep 29, 2024

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