VCV002419005.5 - ClinVar

NM_001330260.2(SCN8A):c.5311G>A (p.Val1771Ile)

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.

(2)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001330260.2(SCN8A):c.5311G>A (p.Val1771Ile)

Variation ID: 2419005 Accession: VCV002419005.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.13 12: 51806797 (GRCh38) [ NCBI UCSC ] 12: 52200581 (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 13, 2023	Feb 20, 2024	Sep 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001330260.2:c.5311G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001317189.1:p.Val1771Ile	missense
NM_014191.4:c.5311G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055006.1:p.Val1771Ile	missense
NM_001177984.3:c.5188G>A	NP_001171455.1:p.Val1730Ile	missense
NM_001369788.1:c.5188G>A	NP_001356717.1:p.Val1730Ile	missense
NM_014191.3:c.5311G>A
NC_000012.12:g.51806797G>A
NC_000012.11:g.52200581G>A
NG_021180.3:g.221840G>A
LRG_1389:g.221840G>A
LRG_1389t1:c.5311G>A	LRG_1389p1:p.Val1771Ile
LRG_1389t2:c.5311G>A	LRG_1389p2:p.Val1771Ile

... more HGVS ... less HGVS

Protein change

V1730I, V1771I

Other names

Canonical SPDI

NC_000012.12:51806796:G:A

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.
SCN8A		No evidence available	No evidence available	GRCh38 GRCh37	2021	2116

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	Uncertain significance (1)	criteria provided, single submitter	May 10, 2022	RCV003112249.4
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 16, 2022	RCV003154287.1

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 (Sep 16, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003842814.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that … (more) Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This substitution is predicted to be within the C-terminal cytoplasmic domain.; This variant is associated with the following publications: (PMID: 31887642, 32090326, 30171078, 30968951) (less)
Uncertain significance (May 10, 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: SCV003786568.3 First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 30968951 Comment: This missense change has been observed in individual(s) with SCN8A-related conditions (PMID: 30968951). In at least one individual the variant was observed to be de … (more) This missense change has been observed in individual(s) with SCN8A-related conditions (PMID: 30968951). In at least one individual the variant was observed to be de novo. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1771 of the SCN8A protein (p.Val1771Ile). This variant is not present in population databases (gnomAD no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This substitution is predicted to be within the C-terminal cytoplasmic domain.; This variant is associated with the following publications: (PMID: 31887642, 32090326, 30171078, 30968951)

Comment:

This missense change has been observed in individual(s) with SCN8A-related conditions (PMID: 30968951). In at least one individual the variant was observed to be de novo. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1771 of the SCN8A protein (p.Val1771Ile). This variant is not present in population databases (gnomAD no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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
The spectrum of intermediate SCN8A-related epilepsy.	Johannesen KM	Epilepsia	2019	PMID: 30968951

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001330260.2(SCN8A):c.5311G>A (p.Val1771Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...