Converted during submission to Likely benign.
ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.1811G>A (p.Arg604His)
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.
(14)
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.
Benign/Likely benign
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001165963.4(SCN1A):c.1811G>A (p.Arg604His)
Variation ID: 68589 Accession: VCV000068589.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q24.3 2: 166043901 (GRCh38) [ NCBI UCSC ] 2: 166900411 (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 Oct 31, 2013 Oct 20, 2024 Jul 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001165963.4:c.1811G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Arg604His missense NM_001165964.3:c.1811G>A NP_001159436.1:p.Arg604His missense NM_001202435.1:c.1811G>A NM_001202435.3:c.1811G>A NP_001189364.1:p.Arg604His missense NM_001353948.2:c.1811G>A NP_001340877.1:p.Arg604His missense NM_001353949.2:c.1811G>A NP_001340878.1:p.Arg604His missense NM_001353950.2:c.1811G>A NP_001340879.1:p.Arg604His missense NM_001353951.2:c.1811G>A NP_001340880.1:p.Arg604His missense NM_001353952.2:c.1811G>A NP_001340881.1:p.Arg604His missense NM_001353954.2:c.1808G>A NP_001340883.1:p.Arg603His missense NM_001353955.2:c.1808G>A NP_001340884.1:p.Arg603His missense NM_001353957.2:c.1811G>A NP_001340886.1:p.Arg604His missense NM_001353958.2:c.1811G>A NP_001340887.1:p.Arg604His missense NM_001353960.2:c.1808G>A NP_001340889.1:p.Arg603His missense NM_001353961.2:c.-615G>A 5 prime UTR NM_006920.6:c.1811G>A NP_008851.3:p.Arg604His missense NR_148667.2:n.2197G>A non-coding transcript variant NC_000002.12:g.166043901C>T NC_000002.11:g.166900411C>T NG_011906.1:g.34739G>A LRG_8:g.34739G>A LRG_8t1:c.1811G>A P35498:p.Arg604His - Protein change
- R604H, R603H
- Other names
-
p.R604H:CGT>CAT
NM_001165963.1(SCN1A):c.1811G>A(p.Arg604His)
NM_001165964.1(SCN1A):c.1811G>A(p.Arg604His)
NM_001202435.1(SCN1A):c.1811G>A(p.Arg604His)
NM_006920.4(SCN1A):c.1811G>A(p.Arg604His)
- Canonical SPDI
- NC_000002.12:166043900:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00140 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00140
The Genome Aggregation Database (gnomAD), exomes 0.00145
Exome Aggregation Consortium (ExAC) 0.00155
1000 Genomes Project 30x 0.00203
Trans-Omics for Precision Medicine (TOPMed) 0.00080
The Genome Aggregation Database (gnomAD) 0.00087
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00108
- 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. |
|||
| SCN1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2245 | 4634 | |
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. |
|---|---|---|---|---|
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
May 28, 2019 | RCV000059465.10 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 14, 2017 | RCV000079561.18 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jun 14, 2016 | RCV000259883.13 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000355074.13 | |
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000434909.25 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV001132420.12 | |
| Benign (1) |
criteria provided, single submitter
|
Jan 25, 2024 | RCV001087094.14 | |
| Benign (1) |
criteria provided, single submitter
|
Jul 24, 2016 | RCV002311541.9 | |
|
SCN1A-related disorder
|
Benign (1) |
no assertion criteria provided
|
Aug 17, 2022 | RCV004537266.2 |
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 Benign
(Feb 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511198.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Converted during submission to Likely benign.
|
|
|
Benign
(Sep 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000242443.6
First in ClinVar: Aug 07, 2015 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
|
Benign
(Jan 10, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000111443.8
First in ClinVar: Jan 22, 2014 Last updated: Apr 09, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Likely benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Severe myoclonic epilepsy in infancy
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001136054.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Benign
(Sep 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001145449.1
First in ClinVar: Jan 18, 2020 Last updated: Jan 18, 2020 |
|
|
|
Likely benign
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Seizure Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000417816.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Benign
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Severe myoclonic epilepsy in infancy
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803506.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
Comment:
This variant is interpreted as a Benign, for Epileptic encephalopathy, early infantile, 6, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => … (more)
This variant is interpreted as a Benign, for Epileptic encephalopathy, early infantile, 6, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:18930999). BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:19589774). (less)
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Generalized epilepsy with febrile seizures plus, type 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001292080.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Migraine, familial hemiplegic, 3
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000417815.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Benign
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000252755.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
|
|
|
Benign
(Jul 24, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000847284.5
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Benign
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV003916156.13
First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024 |
Comment:
SCN1A: BS1, BS2
Number of individuals with the variant: 10
|
|
|
Benign
(Aug 17, 2022)
|
no assertion criteria provided
Method: clinical testing
|
SCN1A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004724154.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
Severe myoclonic epilepsy in infancy
Affected status: not provided
Allele origin:
not provided
|
UniProtKB/Swiss-Prot
Accession: SCV000090990.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
This variant is interpreted as a Benign, for Epileptic encephalopathy, early infantile, 6, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:18930999). BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:19589774).
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
SCN1A: BS1, BS2
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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:
Converted during submission to Likely benign.
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
This variant is interpreted as a Benign, for Epileptic encephalopathy, early infantile, 6, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:18930999). BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:19589774).
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
SCN1A: BS1, BS2
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| SCN1A gene sequencing in 46 Turkish epilepsy patients disclosed 12 novel mutations. | Usluer S | Seizure | 2016 | PMID: 27236449 |
| Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes. | Lal D | PloS one | 2016 | PMID: 26990884 |
| Comprehensive molecular testing in patients with high functioning autism spectrum disorder. | Alvarez-Mora MI | Mutation research | 2016 | PMID: 26845707 |
| Polymorphisms of the SCN1A gene in children and adolescents with primary headache and idiopathic or cryptogenic epilepsy: is there a linkage? | Toldo I | The journal of headache and pain | 2011 | PMID: 21713554 |
| Timing of de novo mutagenesis--a twin study of sodium-channel mutations. | Vadlamudi L | The New England journal of medicine | 2010 | PMID: 20879882 |
| De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin. | Heron SE | Journal of medical genetics | 2010 | PMID: 19589774 |
| Genetic screening of two Tunisian families with generalized epilepsy with febrile seizures plus. | Fendri-Kriaa N | European journal of neurology | 2009 | PMID: 19236456 |
| Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. | Depienne C | Journal of medical genetics | 2009 | PMID: 18930999 |
| A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy. | Escayg A | American journal of human genetics | 2001 | PMID: 11254445 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN1A | - | - | - | - |
Text-mined citations for rs121918769 ...
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 Nov 25, 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.