VCV003254875.1 - ClinVar

NM_001330260.2(SCN8A):c.5282A>G (p.Tyr1761Cys)

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_001330260.2(SCN8A):c.5282A>G (p.Tyr1761Cys)

Variation ID: 3254875 Accession: VCV003254875.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.13 12: 51806768 (GRCh38) [ NCBI UCSC ] 12: 52200552 (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 23, 2024	Jul 23, 2024	Dec 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001330260.2:c.5282A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001317189.1:p.Tyr1761Cys	missense
NM_014191.4:c.5282A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055006.1:p.Tyr1761Cys	missense
NM_001177984.3:c.5159A>G	NP_001171455.1:p.Tyr1720Cys	missense
NM_001369788.1:c.5159A>G	NP_001356717.1:p.Tyr1720Cys	missense
NC_000012.12:g.51806768A>G
NC_000012.11:g.52200552A>G
NG_021180.3:g.221811A>G
LRG_1389:g.221811A>G
LRG_1389t1:c.5282A>G	LRG_1389p1:p.Tyr1761Cys
LRG_1389t2:c.5282A>G	LRG_1389p2:p.Tyr1761Cys

... more HGVS ... less HGVS

Protein change

Y1720C, Y1761C

Other names

Canonical SPDI

NC_000012.12:51806767:A:G

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	2039	2135

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.
Developmental and epileptic encephalopathy, 13	Pathogenic (1)	criteria provided, single submitter	Dec 20, 2023	RCV004595058.1

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 (Dec 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 13 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005087103.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 31904124‚ 34431999 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene, and are associated with cognitive impairment with or without cerebellar ataxia (MIM#614306), and developmental and epileptic encephalopathy 13 (MIM#614558), respectively. In addition, gain of function is speculated for benign familial infantile seizures, 5 (MIM#617080) (PMID: 31904124, OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Tyr1761His) has been observed as de novo in an individual with intellectual disability and seizures (PMID: 34431999). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene, and are associated with cognitive impairment with or without cerebellar ataxia (MIM#614306), and developmental and epileptic encephalopathy 13 (MIM#614558), respectively. In addition, gain of function is speculated for benign familial infantile seizures, 5 (MIM#617080) (PMID: 31904124, OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Tyr1761His) has been observed as de novo in an individual with intellectual disability and seizures (PMID: 34431999). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.	Johannesen KM	Brain : a journal of neurology	2022	PMID: 34431999
Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes.	Gardella E	Epilepsia	2019	PMID: 31904124

Text-mined citations for this variant ...

Record last updated Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_001330260.2(SCN8A):c.5282A>G (p.Tyr1761Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...