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NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln) AND Complex neurodevelopmental disorder

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
May 9, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV003992248.2

Allele description [Variation Report for NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln)]

NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln)

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.5615G>A (p.Arg1872Gln)
Other names:
NM_001330260.2(SCN8A):c.5615G>A
HGVS:
  • NC_000012.12:g.51807101G>A
  • NG_021180.3:g.222144G>A
  • NM_001177984.3:c.5492G>A
  • NM_001330260.2:c.5615G>AMANE SELECT
  • NM_001369788.1:c.5492G>A
  • NM_014191.4:c.5615G>A
  • NP_001171455.1:p.Arg1831Gln
  • NP_001317189.1:p.Arg1872Gln
  • NP_001356717.1:p.Arg1831Gln
  • NP_055006.1:p.Arg1872Gln
  • LRG_1389t1:c.5615G>A
  • LRG_1389t2:c.5615G>A
  • LRG_1389:g.222144G>A
  • LRG_1389p1:p.Arg1872Gln
  • LRG_1389p2:p.Arg1872Gln
  • NC_000012.11:g.52200885G>A
  • NM_001330260.1:c.5615G>A
  • NM_014191.3:c.5615G>A
  • Q9UQD0:p.Arg1872Gln
Protein change:
R1831Q
Links:
UniProtKB: Q9UQD0#VAR_076616; dbSNP: rs796053229
NCBI 1000 Genomes Browser:
rs796053229
Molecular consequence:
  • NM_001177984.3:c.5492G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330260.2:c.5615G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369788.1:c.5492G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014191.4:c.5615G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
  • Decrease in slope of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0034]
  • Mild depolarizing shift of voltage dependence of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0062]
  • Mild hyperpolarizing shift of voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0029]
  • Moderate increase in peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0094]
  • Normal persistent current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0044]
  • Normal rate of recovery from fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0054]
  • Normal resurgent current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0100]
  • Normal slope of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0074]
  • Overall gain-of-function effect with respect to biophysical channel activity [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0140]

Condition(s)

Name:
Complex neurodevelopmental disorder
Identifiers:
MONDO: MONDO:0100038; MedGen: C5568766

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004809229Channelopathy-Associated Epilepsy Research Center
no classification provided
not providednot applicableliterature only

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

SCV005061733ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen
reviewed by expert panel

(ClinGen EpilepsySCN ACMG Specifications SCN8A V1.0.0)		Pathogenic
(May 9, 2024) 		germlinecuration

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
not providednot applicablenot applicablenot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Distinct functional alterations in SCN8A epilepsy mutant channels.

Pan Y, Cummins TR.

J Physiol. 2020 Jan;598(2):381-401. doi: 10.1113/JP278952. Epub 2019 Dec 31.

PubMed [citation]
PMID:
31715021
PMCID:
PMC7216308

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy.

Wagnon JL, Barker BS, Hounshell JA, Haaxma CA, Shealy A, Moss T, Parikh S, Messer RD, Patel MK, Meisler MH.

Ann Clin Transl Neurol. 2016 Feb;3(2):114-23. doi: 10.1002/acn3.276.

PubMed [citation]
PMID:
26900580
PMCID:
PMC4748308

Details of each submission

From Channelopathy-Associated Epilepsy Research Center, SCV004809229.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not applicablenot applicablenot providednot providednot providednot providednot providednot providednot provided

From ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen, SCV005061733.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The c.5615G>A variant in SCN8A is a missense variant predicted to cause a subtitution of arginine by glutamine at amino acid 1872 (p.Arg1872Gln). This variant has been reported as de novo in at least 3 individuals with unconfirmed parental relationships (PMIDs: 2664715, 28333917, 28387369) (PM6) and at least an additional 8 individuals without informative segregation data available (PMIDs: 25568300, 29655203, 29930392, 32509551, 34395220, 30968951) (PS4). Multiple other amino acid substitutions at the same amino acid position have been previously reported and meet pathogenic per these criteria (p.Arg1872Gly, p.Arg1872Trp, p.Arg1872Leu) (PM5). Heterologous expression with voltage clamping assay has shown significant hyperpolarizing shift in voltage dependence of activation and significant depolarizing shift of voltage dependence of fast inactivation (PS3). The variant is rare (1 allele) in the population database, gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM6, PM5, PS3, PM2_Supporting (version 1.0; approved 5/23/23).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024