NM_001330260.2(SCN8A):c.2983A>G (p.Asn995Asp) AND Developmental and epileptic encephalopathy, 13

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 21, 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:: RCV001542340.2

Allele description [Variation Report for NM_001330260.2(SCN8A):c.2983A>G (p.Asn995Asp)]

NM_001330260.2(SCN8A):c.2983A>G (p.Asn995Asp)

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.2983A>G (p.Asn995Asp)

HGVS:

NC_000012.12:g.51768946A>G
NG_021180.3:g.183989A>G
NM_001177984.3:c.2983A>G
NM_001330260.2:c.2983A>GMANE SELECT
NM_001369788.1:c.2983A>G
NM_014191.4:c.2983A>G
NP_001171455.1:p.Asn995Asp
NP_001317189.1:p.Asn995Asp
NP_001356717.1:p.Asn995Asp
NP_055006.1:p.Asn995Asp
LRG_1389t1:c.2983A>G
LRG_1389t2:c.2983A>G
LRG_1389:g.183989A>G
LRG_1389p1:p.Asn995Asp
LRG_1389p2:p.Asn995Asp
NC_000012.11:g.52162730A>G
NM_001330260.1:c.2983A>G
NM_014191.3:c.2983A>G

Protein change:

N995D

Links:

dbSNP: rs1565917769

NCBI 1000 Genomes Browser:

rs1565917769

Molecular consequence:

NM_001177984.3:c.2983A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330260.2:c.2983A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369788.1:c.2983A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014191.4:c.2983A>G - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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Mus musculus tektin like 1 (Tektl1), mRNA
Mus musculus tektin like 1 (Tektl1), mRNA
gi|254553375|ref|NM_027630.1|

Nucleotide
Rattus norvegicus sorting nexin 27 (Snx27), transcript variant 2, mRNA
Rattus norvegicus sorting nexin 27 (Snx27), transcript variant 2, mRNA
gi|158711714|ref|NM_152847.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001761028	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Likely pathogenic (May 21, 2020)	de novo	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001761028

New York Genome Center - CSER-NYCKidSeq

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Likely pathogenic
(May 21, 2020)

de novo

clinical testing

Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	unknown	1	not provided	not provided	1	not provided	clinical testing

Details of each submission

From New York Genome Center - CSER-NYCKidSeq, SCV001761028.1

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

Description

The de novo c.2983A>G (p.Asn995Asp) variant identified in the SCN8A gene substitutes a fully conserved Asparagine for Aspartic Acid at amino acid 995/1981 (coding exon 17/27). This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in this database. In silico algorithms predict this variant to be Deleterious (Provean; score: -4.78) and Damaging (SIFT; score:0.00) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:576451) and to our current knowledge has not been reported in affected individuals in the literature. The p.Asn995 residue is within the second transmembrane domain of SCN8A (UniProtKB:Q9UQD0), where other pathogenic variants have been reported in affected individuals (for Review [PMID:26029160]). Given its presence de novo in the affected individual, its absence in population databases, and prediction of damaging effect on the canonical transcript, the c.2983A>G (p.Asn995Asp) variant identified in the SCN8A gene is reported here as Likely Pathogenic.

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

Last Updated: Sep 29, 2024

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