NM_001330260.2(SCN8A):c.2952C>G (p.Asn984Lys) AND Developmental and epileptic encephalopathy, 13

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 22, 2022
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:: RCV000172909.16

Allele description [Variation Report for NM_001330260.2(SCN8A):c.2952C>G (p.Asn984Lys)]

NM_001330260.2(SCN8A):c.2952C>G (p.Asn984Lys)

Gene:

SCN8A:sodium voltage-gated channel alpha subunit 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.13

Genomic location:

Preferred name:

NM_001330260.2(SCN8A):c.2952C>G (p.Asn984Lys)

HGVS:

NC_000012.12:g.51768915C>G
NG_021180.3:g.183958C>G
NM_001177984.3:c.2952C>G
NM_001330260.2:c.2952C>GMANE SELECT
NM_001369788.1:c.2952C>G
NM_014191.4:c.2952C>G
NP_001171455.1:p.Asn984Lys
NP_001317189.1:p.Asn984Lys
NP_001356717.1:p.Asn984Lys
NP_055006.1:p.Asn984Lys
NP_055006.1:p.Asn984Lys
LRG_1389t1:c.2952C>G
LRG_1389t2:c.2952C>G
LRG_1389:g.183958C>G
LRG_1389p1:p.Asn984Lys
LRG_1389p2:p.Asn984Lys
NC_000012.11:g.52162699C>G
NM_014191.2:c.2952C>G
NM_014191.3:c.2952C>G
Q9UQD0:p.Asn984Lys

Protein change:

N984K; ASN984LYS

Links:

UniProtKB: Q9UQD0#VAR_076607; OMIM: 600702.0008; dbSNP: rs876657399

NCBI 1000 Genomes Browser:

rs876657399

Molecular consequence:

NM_001177984.3:c.2952C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330260.2:c.2952C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369788.1:c.2952C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014191.4:c.2952C>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Moderate hyperpolarizing shift of voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0030]
Normal voltage dependence of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0070]
Overall gain-of-function effect with respect to biophysical channel activity [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0140]

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 13 (DEE13)
Synonyms:: Early infantile epileptic encephalopathy 13; SCN8A-Related Epilepsy
Identifiers:: MONDO: MONDO:0013801; MedGen: C3281191; Orphanet: 442835; OMIM: 614558

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000223891	OMIM	no assertion criteria provided	Pathogenic (May 1, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000298197	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002521823	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25725044, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000223891

OMIM

no assertion criteria provided

Pathogenic
(May 1, 2015)

germline

literature only

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

SCV000298197

GeneReviews

no classification provided

not provided

germline

literature only

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

SCV002521823

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 22, 2022)

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only, clinical testing

Citations

PubMed

De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy.

Blanchard MG, Willemsen MH, Walker JB, Dib-Hajj SD, Waxman SG, Jongmans MC, Kleefstra T, van de Warrenburg BP, Praamstra P, Nicolai J, Yntema HG, Bindels RJ, Meisler MH, Kamsteeg EJ.

J Med Genet. 2015 May;52(5):330-7. doi: 10.1136/jmedgenet-2014-102813. Epub 2015 Feb 27.

PubMed [citation]

PMID:: 25725044
PMCID:: PMC4413743

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000223891.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 7-year-old girl with developmental and epileptic encephalopathy-13 (DEE13; 614558), Blanchard et al. (2015) identified a de novo heterozygous c.2952C-G transversion (c.2952C-G, NM_014191.2) in the SCN8A gene, resulting in an asn984-to-lys (N984K) substitution at a highly conserved residue adjacent to the transmembrane segment of the channel. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutation caused a 10-mV hyperpolarization shift, predicting premature channel opening and neuronal hyperactivity. The findings were consistent with a gain of function. The patient had onset of intractable seizures at 6 weeks of age.

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

From GeneReviews, SCV000298197.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	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

From 3billion, SCV002521823.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25725044). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.38). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SCN8A related disorder (ClinVar ID: VCV000192317 / PMID: 25725044). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25725044). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Nov 3, 2024

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