NM_001330260.2(SCN8A):c.3979A>G (p.Ile1327Val) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 14, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000493549.12

Allele description [Variation Report for NM_001330260.2(SCN8A):c.3979A>G (p.Ile1327Val)]

NM_001330260.2(SCN8A):c.3979A>G (p.Ile1327Val)

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.3979A>G (p.Ile1327Val)

HGVS:

NC_000012.12:g.51786578A>G
NG_021180.3:g.201621A>G
NM_001177984.3:c.3856A>G
NM_001330260.2:c.3979A>GMANE SELECT
NM_001369788.1:c.3856A>G
NM_014191.4:c.3979A>G
NP_001171455.1:p.Ile1286Val
NP_001317189.1:p.Ile1327Val
NP_001356717.1:p.Ile1286Val
NP_055006.1:p.Ile1327Val
LRG_1389t1:c.3979A>G
LRG_1389t2:c.3979A>G
LRG_1389:g.201621A>G
LRG_1389p1:p.Ile1327Val
LRG_1389p2:p.Ile1327Val
NC_000012.11:g.52180362A>G
NM_014191.3:c.3979A>G
Q9UQD0:p.Ile1327Val

Protein change:

I1286V

Links:

UniProtKB: Q9UQD0#VAR_071676; dbSNP: rs879255704

NCBI 1000 Genomes Browser:

rs879255704

Molecular consequence:

NM_001177984.3:c.3856A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330260.2:c.3979A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369788.1:c.3856A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014191.4:c.3979A>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Acceleration of deactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0017]
Decrease in slope of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0034]
Depolarizing shift of voltage dependence of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0060]
Mild hyperpolarizing shift of voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0029]
Normal peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0096]
Normal rate of recovery from fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0054]
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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000583186	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 14, 2024)	germline	clinical testing	Citation Link,
SCV002817220	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Oct 1, 2020)	unknown	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

SCV000583186

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 14, 2024)

germline

clinical testing

Citation Link,

SCV002817220

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Oct 1, 2020)

unknown

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

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000583186.5

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This substitution is predicted to be within the transmembrane segment S5 of the third homologous domain; This variant is associated with the following publications: (PMID: 24352161, 32090326, 35365919, 36007526, 37432431, 35982159, 27375106, 26993267, 25799905)

#	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 Athena Diagnostics, SCV002817220.1

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

Description

This variant occurs de novo in an individual tested at Athena Diagnostics and in published literature (PMID: 26993267, 24352161, 25799905). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests that this variant alters the voltage-gated sodium channel (PMID: 27375106).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

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

Last Updated: Oct 13, 2024

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