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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25473036, 25937001, 29655203)
ClinVar Genomic variation as it relates to human health
NM_001040142.2(SCN2A):c.4877G>A (p.Arg1626Gln)
Germline
Classification
Help
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.
(8)
Help
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001040142.2(SCN2A):c.4877G>A (p.Arg1626Gln)
Variation ID: 207017 Accession: VCV000207017.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q24.3 2: 165388683 (GRCh38) [ NCBI UCSC ] 2: 166245193 (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 Aug 7, 2015 Oct 8, 2024 Aug 26, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001040142.2:c.4877G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035232.1:p.Arg1626Gln missense NM_001371246.1:c.4877G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001358175.1:p.Arg1626Gln missense NM_001040143.2:c.4877G>A NP_001035233.1:p.Arg1626Gln missense NM_001371247.1:c.4877G>A NP_001358176.1:p.Arg1626Gln missense NM_021007.3:c.4877G>A NP_066287.2:p.Arg1626Gln missense NC_000002.12:g.165388683G>A NC_000002.11:g.166245193G>A NG_008143.1:g.154282G>A - Protein change
- R1626Q
- Other names
-
p.R1626Q:CGA>CAA
- Canonical SPDI
- NC_000002.12:165388682:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Increase in ramp current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0130]Increase in slope of fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0073]Mild increase in peak current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0093]Mild-moderate slowing of recovery from fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0056]Mild slowing of fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0049]Moderate depolarizing shift of voltage dependence of fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0063]Normal persistent current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0044]Normal recovery from slow inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0108]Normal slope of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0036]Normal voltage dependence of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0032]
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Global minor allele
frequency (GMAF) HelpThe 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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 26, 2023 | RCV000189169.6 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2023 | RCV000679890.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 4, 2019 | RCV001054289.8 | |
| Likely pathogenic (2) |
no assertion criteria provided
|
Feb 23, 2016 | RCV001265496.2 | |
|
SCN2A-related disorder
|
Likely pathogenic (1) |
no assertion criteria provided
|
Apr 20, 2024 | RCV004734835.1 |
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
(May 19, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
de novo
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280873.1
First in ClinVar: Aug 07, 2015 Last updated: Aug 07, 2015 |
|
|
|
Pathogenic
(Aug 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000242801.12
First in ClinVar: Aug 07, 2015 Last updated: Aug 31, 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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25473036, 25937001, 29655203) (less)
|
|
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Pathogenic
(Jan 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 11
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000807294.4
First in ClinVar: Sep 17, 2018 Last updated: Mar 18, 2023 |
|
|
|
Pathogenic
(Dec 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 11
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764872.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Brain atrophy (present) , Epileptic encephalopathy (present)
|
|
|
Pathogenic
(Dec 04, 2019)
|
criteria provided, single submitter
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: SCV001218597.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are … (more)
For these reasons, this variant has been classified as Pathogenic. 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"). This variant has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 25937001, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207017). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 1626 of the SCN2A protein (p.Arg1626Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. (less)
|
|
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Likely pathogenic
(Feb 23, 2016)
|
no assertion criteria provided
Method: provider interpretation
|
Complex neurodevelopmental disorder
Affected status: yes
Allele origin:
unknown
|
GenomeConnect - Simons Searchlight
Accession: SCV001443640.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-02-23 and interpreted as Likely Pathogenic. Variant was … (more)
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-02-23 and interpreted as Likely Pathogenic. Variant was initially reported on 2014-03-26 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. (less)
Sex: male
|
|
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Likely pathogenic
(Apr 20, 2024)
|
no assertion criteria provided
Method: clinical testing
|
SCN2A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005360688.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The SCN2A c.4877G>A variant is predicted to result in the amino acid substitution p.Arg1626Gln. This variant has been reported in patients with SCN2A related disorders, … (more)
The SCN2A c.4877G>A variant is predicted to result in the amino acid substitution p.Arg1626Gln. This variant has been reported in patients with SCN2A related disorders, including as a de novo finding (Soden et al. 2014. PubMed ID: 25473036; Willig et al. 2015. PubMed ID: 25937001; Lindy et al. 2018. PubMed ID: 29655203; https://www.ncbi.nlm.nih.gov/clinvar/variation/207017/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)
|
|
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not provided
(-)
|
no classification provided
Method: literature only
|
Complex neurodevelopmental disorder
Affected status: not applicable
Allele origin:
not applicable
|
Channelopathy-Associated Epilepsy Research Center
Accession: SCV004232407.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Method: Automated patch clamp
Result:
mild increase in peak current; normal voltage dependence of activation; normal slope of activation; moderate depolarizing shift of voltage of dependence of fast inactivation; increase in slope of fast inactivation; mild-moderate slowing of recovery from fast inactivation; normal rate of recovery from slow inactivation;mild slowing of fast inactivation; increase in ramp current;normal persistent current
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. 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"). This variant has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 25937001, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207017). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 1626 of the SCN2A protein (p.Arg1626Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-02-23 and interpreted as Likely Pathogenic. Variant was initially reported on 2014-03-26 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.
Comment:
The SCN2A c.4877G>A variant is predicted to result in the amino acid substitution p.Arg1626Gln. This variant has been reported in patients with SCN2A related disorders, including as a de novo finding (Soden et al. 2014. PubMed ID: 25473036; Willig et al. 2015. PubMed ID: 25937001; Lindy et al. 2018. PubMed ID: 29655203; https://www.ncbi.nlm.nih.gov/clinvar/variation/207017/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Mild increase in peak current
Normal voltage dependence of activation
Normal slope of activation
Moderate depolarizing shift of voltage dependence of fast inactivation
Increase in slope of fast inactivation
Mild-moderate slowing of recovery from fast inactivation
Normal recovery from slow inactivation
Mild slowing of fast inactivation
Increase in ramp current
Normal persistent current
|
|
|
Channelopathy-Associated Epilepsy Research Center
Accession: SCV004232407.1
|
|
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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25473036, 25937001, 29655203)
Comment:
For these reasons, this variant has been classified as Pathogenic. 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"). This variant has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 25937001, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207017). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 1626 of the SCN2A protein (p.Arg1626Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-02-23 and interpreted as Likely Pathogenic. Variant was initially reported on 2014-03-26 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.
Comment:
The SCN2A c.4877G>A variant is predicted to result in the amino acid substitution p.Arg1626Gln. This variant has been reported in patients with SCN2A related disorders, including as a de novo finding (Soden et al. 2014. PubMed ID: 25473036; Willig et al. 2015. PubMed ID: 25937001; Lindy et al. 2018. PubMed ID: 29655203; https://www.ncbi.nlm.nih.gov/clinvar/variation/207017/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties. | Thompson CH | The Journal of general physiology | 2023 | PMID: 37578743 |
| Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. | Willig LK | The Lancet. Respiratory medicine | 2015 | PMID: 25937001 |
Text-mined citations for rs796053155 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.