VCV002094348.2 - ClinVar

NM_001165963.4(SCN1A):c.3641T>A (p.Ile1214Lys)

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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001165963.4(SCN1A):c.3641T>A (p.Ile1214Lys)

Variation ID: 2094348 Accession: VCV002094348.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 166013808 (GRCh38) [ NCBI UCSC ] 2: 166870318 (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	Feb 8, 2023	Feb 20, 2024	Feb 7, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001165963.4:c.3641T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001159435.1:p.Ile1214Lys	missense
NM_001165964.3:c.3557T>A	NP_001159436.1:p.Ile1186Lys	missense
NM_001202435.3:c.3641T>A	NP_001189364.1:p.Ile1214Lys	missense
NM_001353948.2:c.3641T>A	NP_001340877.1:p.Ile1214Lys	missense
NM_001353949.2:c.3608T>A	NP_001340878.1:p.Ile1203Lys	missense
NM_001353950.2:c.3608T>A	NP_001340879.1:p.Ile1203Lys	missense
NM_001353951.2:c.3608T>A	NP_001340880.1:p.Ile1203Lys	missense
NM_001353952.2:c.3608T>A	NP_001340881.1:p.Ile1203Lys	missense
NM_001353954.2:c.3605T>A	NP_001340883.1:p.Ile1202Lys	missense
NM_001353955.2:c.3605T>A	NP_001340884.1:p.Ile1202Lys	missense
NM_001353957.2:c.3557T>A	NP_001340886.1:p.Ile1186Lys	missense
NM_001353958.2:c.3557T>A	NP_001340887.1:p.Ile1186Lys	missense
NM_001353960.2:c.3554T>A	NP_001340889.1:p.Ile1185Lys	missense
NM_001353961.2:c.1199T>A	NP_001340890.1:p.Ile400Lys	missense
NM_006920.6:c.3608T>A	NP_008851.3:p.Ile1203Lys	missense
NR_148667.2:n.3994T>A		non-coding transcript variant
NC_000002.12:g.166013808A>T
NC_000002.11:g.166870318A>T
NG_011906.1:g.64832T>A
LRG_8:g.64832T>A
LRG_8t1:c.3608T>A	LRG_8p1:p.Ile1203Lys

... more HGVS ... less HGVS

Protein change

I1185K, I1186K, I1214K, I1202K, I400K, I1203K

Other names

Canonical SPDI

NC_000002.12:166013807:A:T

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

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.
SCN1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2241	4627
LOC102724058	-	-	-	GRCh38	-	2327

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	Feb 7, 2022	RCV003021295.3

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 (Feb 07, 2022)	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: SCV003312323.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 22848613‚ 31864146 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1214 of the SCN1A protein (p.Ile1214Lys). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1214 of the SCN1A protein (p.Ile1214Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (Invitae). 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) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. This variant disrupts the p.Ile1214 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22848613, 31864146). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1214 of the SCN1A protein (p.Ile1214Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (Invitae). 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) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. This variant disrupts the p.Ile1214 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22848613, 31864146). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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
A single-center, retrospective analysis of genotype-phenotype correlations in children with Dravet syndrome.	Gertler TS	Seizure	2020	PMID: 31864146
Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome.	Kwong AK	PloS one	2012	PMID: 22848613

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001165963.4(SCN1A):c.3641T>A (p.Ile1214Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...