VCV002499548.3 - ClinVar

NM_001330260.2(SCN8A):c.5284A>C (p.Ile1762Leu)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

2 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001330260.2(SCN8A):c.5284A>C (p.Ile1762Leu)

Variation ID: 2499548 Accession: VCV002499548.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.13 12: 51806770 (GRCh38) [ NCBI UCSC ] 12: 52200554 (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	Apr 30, 2023	Apr 13, 2025	Aug 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001330260.2:c.5284A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001317189.1:p.Ile1762Leu	missense
NM_014191.4:c.5284A>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055006.1:p.Ile1762Leu	missense
NM_001177984.3:c.5161A>C	NP_001171455.1:p.Ile1721Leu	missense
NM_001369788.1:c.5161A>C	NP_001356717.1:p.Ile1721Leu	missense
NC_000012.12:g.51806770A>C
NC_000012.11:g.52200554A>C
NG_021180.3:g.221813A>C
LRG_1389:g.221813A>C
LRG_1389t1:c.5284A>C	LRG_1389p1:p.Ile1762Leu
LRG_1389t2:c.5284A>C	LRG_1389p2:p.Ile1762Leu

... more HGVS ... less HGVS

Protein change

I1721L, I1762L

Other names

Canonical SPDI

NC_000012.12:51806769:A:C

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

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: CA384885184 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	2204	2308

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.
Cognitive impairment with or without cerebellar ataxia	Pathogenic (1)	criteria provided, single submitter	Apr 20, 2023	RCV003223477.2
Developmental and epileptic encephalopathy, 13	Likely pathogenic (1)	criteria provided, single submitter	Aug 17, 2023	RCV005254751.2

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 (Apr 20, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cognitive impairment with or without cerebellar ataxia Affected status: yes Allele origin: de novo	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003918921.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023
Likely pathogenic (Aug 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 13 Affected status: yes Allele origin: germline	3billion Accession: SCV005904357.1 First in ClinVar: Apr 13, 2025 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 27270488 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 27270488, 35188110). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.92 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SCN8A related disorder (ClinVar ID: VCV002499548). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 27270488, 35188110). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.92 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SCN8A related disorder (ClinVar ID: VCV002499548). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
SCN8A encephalopathy: Research progress and prospects.	Meisler MH	Epilepsia	2016	PMID: 27270488

Text-mined citations for this variant ...

Record last updated Apr 20, 2025

ClinVar Genomic variation as it relates to human health

NM_001330260.2(SCN8A):c.5284A>C (p.Ile1762Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...