NM_001165963.4(SCN1A):c.4837A>G (p.Ile1613Val) AND Generalized epilepsy with febrile seizures plus, type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 11, 2020
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:: RCV002471752.1

Allele description [Variation Report for NM_001165963.4(SCN1A):c.4837A>G (p.Ile1613Val)]

NM_001165963.4(SCN1A):c.4837A>G (p.Ile1613Val)

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.4837A>G (p.Ile1613Val)

HGVS:

NC_000002.12:g.165994161T>C
NG_011906.1:g.84479A>G
NM_001165963.4:c.4837A>GMANE SELECT
NM_001165964.3:c.4753A>G
NM_001202435.3:c.4837A>G
NM_001353948.2:c.4837A>G
NM_001353949.2:c.4804A>G
NM_001353950.2:c.4804A>G
NM_001353951.2:c.4804A>G
NM_001353952.2:c.4804A>G
NM_001353954.2:c.4801A>G
NM_001353955.2:c.4801A>G
NM_001353957.2:c.4753A>G
NM_001353958.2:c.4753A>G
NM_001353960.2:c.4750A>G
NM_001353961.2:c.2395A>G
NM_006920.6:c.4804A>G
NP_001159435.1:p.Ile1613Val
NP_001159436.1:p.Ile1585Val
NP_001189364.1:p.Ile1613Val
NP_001340877.1:p.Ile1613Val
NP_001340878.1:p.Ile1602Val
NP_001340879.1:p.Ile1602Val
NP_001340880.1:p.Ile1602Val
NP_001340881.1:p.Ile1602Val
NP_001340883.1:p.Ile1601Val
NP_001340884.1:p.Ile1601Val
NP_001340886.1:p.Ile1585Val
NP_001340887.1:p.Ile1585Val
NP_001340889.1:p.Ile1584Val
NP_001340890.1:p.Ile799Val
NP_008851.3:p.Ile1602Val
NP_008851.3:p.Ile1602Val
LRG_8t1:c.4804A>G
LRG_8:g.84479A>G
LRG_8p1:p.Ile1602Val
NC_000002.11:g.166850671T>C
NM_006920.4:c.4804A>G
NR_148667.2:n.5254A>G

Protein change:

I1584V

Molecular consequence:

NM_001165963.4:c.4837A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.4753A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.4837A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.4837A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.4804A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.4804A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.4804A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.4804A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.4801A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.4801A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.4753A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.4753A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.4750A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.2395A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.4804A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.5254A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Generalized epilepsy with febrile seizures plus, type 2 (GEFSP2)
Synonyms:: GEFS+, TYPE 2
Identifiers:: MONDO: MONDO:0011461; MedGen: C1858673; Orphanet: 36387; OMIM: 604403

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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002766660	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 11, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20194124, 28488083, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002766660

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 11, 2020)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

NaV1.1 channels and epilepsy.

Catterall WA, Kalume F, Oakley JC.

J Physiol. 2010 Jun 1;588(Pt 11):1849-59. doi: 10.1113/jphysiol.2010.187484. Epub 2010 Mar 1. Review.

PubMed [citation]

PMID:: 20194124
PMCID:: PMC2901973

Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy.

Wei F, Yan LM, Su T, He N, Lin ZJ, Wang J, Shi YW, Yi YH, Liao WP.

Neurosci Bull. 2017 Aug;33(4):455-477. doi: 10.1007/s12264-017-0134-1. Epub 2017 May 9. Review.

PubMed [citation]

PMID:: 28488083
PMCID:: PMC5567559

See all PubMed Citations (3)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766660.1

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

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (PMID:28488083). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine (exon 25). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (pore region repeat IV domain; UniProt, PMID:20194124). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

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

Last Updated: Dec 24, 2022

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