VCV000207119.30 - ClinVar

NM_001330260.2(SCN8A):c.4423G>A (p.Gly1475Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001330260.2(SCN8A):c.4423G>A (p.Gly1475Arg)

Variation ID: 207119 Accession: VCV000207119.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.13 12: 51790401 (GRCh38) [ NCBI UCSC ] 12: 52184185 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 24, 2016	Oct 20, 2024	Oct 3, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001330260.2:c.4423G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001317189.1:p.Gly1475Arg	missense
NM_014191.4:c.4423G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055006.1:p.Gly1475Arg	missense
NM_001177984.3:c.4300G>A	NP_001171455.1:p.Gly1434Arg	missense
NM_001369788.1:c.4300G>A	NP_001356717.1:p.Gly1434Arg	missense
NC_000012.12:g.51790401G>A
NC_000012.11:g.52184185G>A
NG_021180.3:g.205444G>A
LRG_1389:g.205444G>A
LRG_1389t1:c.4423G>A	LRG_1389p1:p.Gly1475Arg
LRG_1389t2:c.4423G>A	LRG_1389p2:p.Gly1475Arg

... more HGVS ... less HGVS

Protein change

G1475R, G1434R

Other names

p.G1475R:GGA>AGA

Canonical SPDI

NC_000012.12:51790400:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Normal slope of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0036]

Normal voltage dependence of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0032]

Normal fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0047]

Normal peak current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0096]

Overall gain-of-function effect with respect to biophysical channel activity; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0140]

Severe increase in persistent current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0043]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA318276 dbSNP: rs796053216 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SCN8A		No evidence available	No evidence available	GRCh38 GRCh37	2030	2126

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Oct 3, 2023	RCV000462091.10
Developmental and epileptic encephalopathy, 13	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 3, 2022	RCV000500598.7
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 1, 2022	RCV000189277.20
Epilepsy	Likely pathogenic (1)	criteria provided, single submitter	Nov 6, 2017	RCV000627041.4
Epileptic encephalopathy	Likely pathogenic (1)	criteria provided, single submitter	Nov 16, 2016	RCV000416962.3
Complex neurodevelopmental disorder	not provided (1)	no classification provided	-	RCV003992219.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Early infantile epileptic encephalopathy with suppression bursts Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000544813.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 28492532‚ 27864847‚ 28923014‚ 30171078‚ 30615093 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1475 of the SCN8A protein (p.Gly1475Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1475 of the SCN8A protein (p.Gly1475Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27864847, 28923014, 30171078). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207119). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN8A protein function. Experimental studies have shown that this missense change affects SCN8A function (PMID: 30615093). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Nov 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epileptic encephalopathy Affected status: yes Allele origin: de novo	Neurogenetics Laboratory - MEYER, AOU Meyer Accession: SCV000494529.1 First in ClinVar: Feb 12, 2017 Last updated: Feb 12, 2017	Family history: no
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 13 Affected status: yes Allele origin: germline	3billion Accession: SCV002058693.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Comment: he variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same … (more) he variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000207119, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.75, 3CNET: 0.972, PP3_P). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 13 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Brisk reflexes (present) , Clinodactyly of the 5th finger (present) , Seizure (present) , Gingival overgrowth (present) , Happy demeanor (present) , Hepatomegaly (present) , … (more) Brisk reflexes (present) , Clinodactyly of the 5th finger (present) , Seizure (present) , Gingival overgrowth (present) , Happy demeanor (present) , Hepatomegaly (present) , Hypertonia (present) , Intellectual disability, profound (present) , Developmental regression (present) , Open mouth (present) , Protruding ear (present) , Achilles tendon contracture (present) (less)
Likely pathogenic (Oct 29, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epileptic encephalopathy, early infantile, 13 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000596983.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Pathogenic (May 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002545036.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: SCN8A: PM1, PM2, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (May 19, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242909.12 First in ClinVar: Aug 07, 2015 Last updated: Jul 24, 2016	Comment: The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); … (more) The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29235621, 30776697, 27864847, 29128679, 28923014, 29429461, 30171078, 30615093, 31402610, 32090326, 32040247) (less)
Likely pathogenic (Nov 06, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizure Disorders Affected status: yes Allele origin: de novo	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000747746.2 First in ClinVar: May 13, 2018 Last updated: Dec 11, 2022	Comment: This variant was identified in a mosaic state in a young female patient with epilepsy. Age: 10-19 years Sex: female
not provided (-)	no classification provided Method: literature only	Complex neurodevelopmental disorder Affected status: not applicable Allele origin: not applicable	Channelopathy-Associated Epilepsy Research Center Accession: SCV004809331.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (1) PubMed: 31402610 Method: whole-cell patch-clamp recording Result: Normal peak current;Normal voltage dependence of activation;Normal slope of activation;Severe increase in persistent current;Normal fast inactivation;Overall gain-of-function effect with respect to biophysical channel activity

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1475 of the SCN8A protein (p.Gly1475Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27864847, 28923014, 30171078). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207119). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN8A protein function. Experimental studies have shown that this missense change affects SCN8A function (PMID: 30615093). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

he variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000207119, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.75, 3CNET: 0.972, PP3_P). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 13 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29235621, 30776697, 27864847, 29128679, 28923014, 29429461, 30171078, 30615093, 31402610, 32090326, 32040247)

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Normal peak current (FENICS-0096) Normal voltage dependence of activation (FENICS-0032) Normal slope of activation (FENICS-0036) Severe increase in persistent current (FENICS-0043) Normal fast inactivation (FENICS-0047) Overall gain-of-function effect with respect to biophysical channel activity (FENICS-0140)	whole-cell patch-clamp recording	Normal peak current;Normal voltage dependence of activation;Normal slope of activation;Severe increase in persistent current;Normal fast inactivation;Overall gain-of-function effect with respect to biophysical channel activity	Channelopathy-Associated Epilepsy Research Center Accession: SCV004809331.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A single-center SCN8A-related epilepsy cohort: clinical, genetic, and physiologic characterization.	Zaman T	Annals of clinical and translational neurology	2019	PMID: 31402610
Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability.	Liu Y	Brain : a journal of neurology	2019	PMID: 30615093
The phenotype of SCN8A developmental and epileptic encephalopathy.	Gardella E	Neurology	2018	PMID: 30171078
SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures.	Wang J	BMC medical genetics	2017	PMID: 28923014
Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.	Parrini E	Human mutation	2017	PMID: 27864847

Text-mined citations for rs796053216 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001330260.2(SCN8A):c.4423G>A (p.Gly1475Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs796053216 ...