VCV002922025.2 - ClinVar

NM_001040142.2(SCN2A):c.1135C>T (p.Arg379Cys)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001040142.2(SCN2A):c.1135C>T (p.Arg379Cys)

Variation ID: 2922025 Accession: VCV002922025.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 165313720 (GRCh38) [ NCBI UCSC ] 2: 166170230 (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 29, 2024	Oct 8, 2024	Jan 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001040142.2:c.1135C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035232.1:p.Arg379Cys	missense
NM_001371246.1:c.1135C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001358175.1:p.Arg379Cys	missense
NM_001040143.2:c.1135C>T	NP_001035233.1:p.Arg379Cys	missense
NM_001371247.1:c.1135C>T	NP_001358176.1:p.Arg379Cys	missense
NM_021007.2:c.1135C>T
NM_021007.3:c.1135C>T	NP_066287.2:p.Arg379Cys	missense
NC_000002.12:g.165313720C>T
NC_000002.11:g.166170230C>T
NG_008143.1:g.79319C>T

... more HGVS ... less HGVS

Protein change

R379C

Other names

Canonical SPDI

NC_000002.12:165313719:C: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.
SCN2A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2608	2683

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, 11 Seizures, benign familial infantile, 3	Likely pathogenic (1)	criteria provided, single submitter	Jan 7, 2024	RCV003783047.2
SCN2A-related disorder	Uncertain significance (1)	no assertion criteria provided	Mar 22, 2024	RCV004736390.1

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.
Likely pathogenic (Jan 07, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Seizures, benign familial infantile, 3 Developmental and epileptic encephalopathy, 11 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004603334.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 28256214‚ 35348308 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 379 of the SCN2A protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 379 of the SCN2A protein (p.Arg379Cys). This variant is present in population databases (rs768403673, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. 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 SCN2A protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg379 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28256214, 35348308). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Uncertain significance (Mar 22, 2024)	no assertion criteria provided Method: clinical testing	SCN2A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005341681.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The SCN2A c.1135C>T variant is predicted to result in the amino acid substitution p.Arg379Cys. To our knowledge, this variant has not been reported in the … (more) The SCN2A c.1135C>T variant is predicted to result in the amino acid substitution p.Arg379Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. A different missense variant affecting the same amino acid (p.Arg379His) has been found to be de novo in two individuals with autism spectrum disorder and neurodevelopmental delay (De Rubeis et al. 2014. PubMed ID: 25363760; Mangano et al. 2022. PubMed ID: 35348308). At this time, the clinical significance of the c.1135C>T (p.Arg379Cys) variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 379 of the SCN2A protein (p.Arg379Cys). This variant is present in population databases (rs768403673, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. 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 SCN2A protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg379 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28256214, 35348308). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

The SCN2A c.1135C>T variant is predicted to result in the amino acid substitution p.Arg379Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. A different missense variant affecting the same amino acid (p.Arg379His) has been found to be de novo in two individuals with autism spectrum disorder and neurodevelopmental delay (De Rubeis et al. 2014. PubMed ID: 25363760; Mangano et al. 2022. PubMed ID: 35348308). At this time, the clinical significance of the c.1135C>T (p.Arg379Cys) variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Commonalities and distinctions between two neurodevelopmental disorder subtypes associated with SCN2A and SCN8A variants and literature review.	Mangano GD	Molecular genetics & genomic medicine	2022	PMID: 35348308
Opposing Effects on Na(V)1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures.	Ben-Shalom R	Biological psychiatry	2017	PMID: 28256214

Text-mined citations for this variant ...

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_001040142.2(SCN2A):c.1135C>T (p.Arg379Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...