The SCN1B c.363C>G (p.Cys121Trp) variant is a missense variant that has been reported in at least three studies in which it is identified in a heterozygous state in at least 45 individuals from several large multi-generation families with generalized epilepsy with febrile seizures plus (GEFS+) exhibiting a range of seizure types. Seizure types included febrile, febrile seizures plus, absence and generalized tonic clonic seizures, temporal lobe epilepsy, myoclonic-astatic epilepsy and unclassified seizures (Wallace et al. 1998; Wallace et al. 2002; Scheffer et al. 2007). The p.Cys121Trp variant is also found in a heterozygous state in multiple unaffected individuals supporting incomplete penetrance of up to 60% as noted by Wallace et al. (1998), or the presence of other factors that may modify the phenotype (Scheffer et al. 2007; Carvill et al. 2014). The p.Cys121Trp variant is reported at a frequency of 0.0000310 in the European (non-Finnish) population of the Genome Aggregation Database which may be consistent with reduced penetrance. The p.Cys121Trp variant affects a highly conserved cysteine residue and putatively disrupts a disulphide bridge in the extracellular domain of the protein that maintains the structure of an extracellular immunoglobulin-like fold. Functional studies in mice expressing the Scn1b-C121W (Scn1b+/W) allele compared to mice heterozygous for the Scn1b-null allele (Scn1b+/-) demonstrated the mice expressing the Scn1b+/W allele were more susceptible to hyperthermia-induced convulsions. The same study also demonstrated that the variant protein was expressed at lower levels in the brain (approximately 50% that of wild type) and may be incompletely glycosylated resulting in abnormal subcellular localization of the protein (Kruger et al. 2016). The variant is suggested to result in a deleterious gain-of-function (Kruger et al. 2016). Based on the collective evidence and application of the ACMG criteria, the p.Cys121Trp variant is classified as pathogenic for generalized epilepsy with febrile seizures plus.
ClinVar Genomic variation as it relates to human health
NM_001037.5(SCN1B):c.363C>G (p.Cys121Trp)
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.
(16)
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/Likely pathogenic
16
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001037.5(SCN1B):c.363C>G (p.Cys121Trp)
Variation ID: 9252 Accession: VCV000009252.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.11 19: 35033654 (GRCh38) [ NCBI UCSC ] 19: 35524558 (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 Apr 4, 2013 Oct 8, 2024 Jan 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001037.5:c.363C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001028.1:p.Cys121Trp missense NM_001321605.2:c.264C>G NP_001308534.1:p.Cys88Trp missense NM_199037.5:c.363C>G NP_950238.1:p.Cys121Trp missense NC_000019.10:g.35033654C>G NC_000019.9:g.35524558C>G NG_013359.1:g.7967C>G LRG_420:g.7967C>G LRG_420t1:c.363C>G LRG_420p1:p.Cys121Trp Q07699:p.Cys121Trp - Protein change
- C121W, C88W
- Other names
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p.C121W:TGC>TGG
- Canonical SPDI
- NC_000019.10:35033653:C:G
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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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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- 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. |
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| SCN1B | No evidence available | No evidence available |
GRCh38 GRCh37 |
575 | 596 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 16, 2021 | RCV000009834.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 18, 2011 | RCV000030434.10 | |
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
May 24, 2023 | RCV000171041.28 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 17, 2014 | RCV000184010.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 25, 2024 | RCV000646741.15 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2022 | RCV000763042.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 22, 2022 | RCV002316188.10 | |
|
SCN1B-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Oct 29, 2023 | RCV004532319.2 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Aug 25, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Epilepsy, generalized, with febrile seizures plus, type 1
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000596954.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
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Pathogenic
(Mar 29, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000340270.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
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Likely pathogenic
(Jun 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501571.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
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Pathogenic
(Aug 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003825468.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Dec 17, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Atrial fibrillation, familial, 13
Affected status: yes
Allele origin:
germline
|
Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Accession: SCV000236524.2
First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015 |
|
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Pathogenic
(Dec 31, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000615050.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
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Pathogenic
(Feb 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Generalized epilepsy with febrile seizures plus, type 1
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV001786600.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
The SCN1B c.363C>G (p.Cys121Trp) variant is a missense variant that has been reported in at least three studies in which it is identified in a … (more)
The SCN1B c.363C>G (p.Cys121Trp) variant is a missense variant that has been reported in at least three studies in which it is identified in a heterozygous state in at least 45 individuals from several large multi-generation families with generalized epilepsy with febrile seizures plus (GEFS+) exhibiting a range of seizure types. Seizure types included febrile, febrile seizures plus, absence and generalized tonic clonic seizures, temporal lobe epilepsy, myoclonic-astatic epilepsy and unclassified seizures (Wallace et al. 1998; Wallace et al. 2002; Scheffer et al. 2007). The p.Cys121Trp variant is also found in a heterozygous state in multiple unaffected individuals supporting incomplete penetrance of up to 60% as noted by Wallace et al. (1998), or the presence of other factors that may modify the phenotype (Scheffer et al. 2007; Carvill et al. 2014). The p.Cys121Trp variant is reported at a frequency of 0.0000310 in the European (non-Finnish) population of the Genome Aggregation Database which may be consistent with reduced penetrance. The p.Cys121Trp variant affects a highly conserved cysteine residue and putatively disrupts a disulphide bridge in the extracellular domain of the protein that maintains the structure of an extracellular immunoglobulin-like fold. Functional studies in mice expressing the Scn1b-C121W (Scn1b+/W) allele compared to mice heterozygous for the Scn1b-null allele (Scn1b+/-) demonstrated the mice expressing the Scn1b+/W allele were more susceptible to hyperthermia-induced convulsions. The same study also demonstrated that the variant protein was expressed at lower levels in the brain (approximately 50% that of wild type) and may be incompletely glycosylated resulting in abnormal subcellular localization of the protein (Kruger et al. 2016). The variant is suggested to result in a deleterious gain-of-function (Kruger et al. 2016). Based on the collective evidence and application of the ACMG criteria, the p.Cys121Trp variant is classified as pathogenic for generalized epilepsy with febrile seizures plus. (less)
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pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation
|
Generalized Epilepsy and Febrile Seizures
(autosomal dominant)
Affected status: yes
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053103.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 28, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 3
Observation 2:
Number of individuals with the variant: 14
Observation 3:
Number of individuals with the variant: 6
Observation 4:
Number of individuals with the variant: 6
Observation 5:
Number of individuals with the variant: 14
Observation 6:
Number of individuals with the variant: 1
|
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Pathogenic
(Nov 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Generalized epilepsy with febrile seizures plus, type 1
Brugada syndrome 5 Atrial fibrillation, familial, 13 Developmental and epileptic encephalopathy, 52
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893521.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Generalized epilepsy with febrile seizures plus, type 1
Developmental and epileptic encephalopathy, 52 Brugada syndrome 5 Atrial fibrillation, familial, 13 Brugada syndrome 5
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920421.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
This variant has been reported in the literature and in public databases in numerous individuals with generalized epilepsy with febrile seizures plus (GEFS+), and has … (more)
This variant has been reported in the literature and in public databases in numerous individuals with generalized epilepsy with febrile seizures plus (GEFS+), and has been shown to segregate with GEFS+ in multiple large families, though it does appear to exhibit incomplete penetrance (Selected publications: Wallace 1998 PMID: 9697698; Scheffer 2007 PMID: 17020904; Butler 2017 PMID: 29056246; ClinVar Variation ID: 9252). However, this variant was also noted to not segregate with the febrile seizures phenotype in several individuals in one of the large families studied (Wallace 1998 PMID: 9697698). Of note, this variant has not been reported in association with cardiac arrhythmia. This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.003% [4/129198]; https://gnomad.broadinstitute.org/variant/19-35524558-C-G?dataset=gnomad_r2_1); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, incomplete penetrance, and/or variable expressivity. This variant is well characterized functionally, with in vitro studies demonstrating that this variant alters sodium channel activity, specifically temperature-dependent hyperexcitability (Selected publications: Wallace 1998 PMID: 9697698; Meadows 2002 PMID: 12486163; Tammaro 2002 PMID: 11866477; Egri 2012 PMID: 22292491). Mouse models with this variant were found to have increased susceptibility to hyperthermia-induced convulsions compared to those with the wild-type sodium channel (Kruger 2016 PMID: 27277800). This variant alters a cysteine residue that is involved in a disulfide bridge predicted to stabilize the extracellular immunoglobulin domain of the encoded protein (Wallace 1998 PMID: 9697698; Barbieri 2012 PMID: 22425777). Evolutionary conservation and computational predictive tools further support that this variant impacts the protein. In summary, this variant is classified as pathogenic. (less)
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Pathogenic
(May 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000223605.20
First in ClinVar: May 23, 2015 Last updated: Jun 03, 2023 |
Comment:
Published functional studies demonstrate altered channel function (Wallace et al., 1998; Meadows et al., 2002; Barbieri et al., 2012; Egri et al., 2012; Baroni et … (more)
Published functional studies demonstrate altered channel function (Wallace et al., 1998; Meadows et al., 2002; Barbieri et al., 2012; Egri et al., 2012; Baroni et al., 2013; Kruger et al., 2016); Reported previously in an individual with late onset episodic ataxia; segregation analysis not performed (Maksemous et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 23584539, 9697698, 12011299, 27216889, 22425777, 11866477, 12486163, 22292491, 24065921, 23527921, 17020904, 28070485, 28488083, 28717674, 29056246, 29620010, 30921204, 29263209, 29992740, 29661262, 29307654, 29335582, 31709768, 31211177, 32303391, 33526774, 33301879, 33841294, 34583279, 31440721, 32466254, 36288729, 24623842, 27277800) (less)
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 5
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000768526.6
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 121 of the SCN1B … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 121 of the SCN1B protein (p.Cys121Trp). This variant is present in population databases (rs104894718, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant SCN1B-related conditions (PMID: 9697698, 12011299, 17020904). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9252). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN1B function (PMID: 20628201, 25421039, 27277800, 28331474). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000851613.4
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.C121W pathogenic mutation (also known as c.363C>G), located in coding exon 3 of the SCN1B gene, results from a C to G substitution at … (more)
The p.C121W pathogenic mutation (also known as c.363C>G), located in coding exon 3 of the SCN1B gene, results from a C to G substitution at nucleotide position 363. The cysteine at codon 121 is replaced by tryptophan, an amino acid with highly dissimilar properties. In three separate studies, with over 100 individuals tested, this alteration was shown to significantly segregate with disease with reduced penetrance (62-76%). In total, it was detected in 44 individuals with a variety of seizure types, including: febrile, generalized epilepsy with febrile seizures plus (GEFS+), afebrile, generalized tonic clonic, (GTC), absence, temporal lobe, and Dravet syndrome (Wallace RH et al. Nat. Genet., 1998 Aug;19:366-70; Wallace RH et al. Neurology, 2002 May;58:1426-9; Scheffer IE et al. Brain, 2007 Jan;130:100-9; Carvill GL et al. Neurology, 2014 Apr;82:1245-53). In addition, several in vitro and in vivo studies indicate that this alteration results in aberrant channel function, more specifically, thermal sensitive hyperexcitability (Barbieri R et al. Biochem. Biophys. Res. Commun., 2012 Apr;420:364-7; Meadows LS et al. J. Neurosci., 2002 Dec;22:10699-709; Tammaro P et al. Biochem. Biophys. Res. Commun., 2002 Mar;291:1095-101; Egri C et al. Epilepsia, 2012 Mar;53:494-505; Kruger LC et al. J. Neurosci., 2016 Jun;36:6213-24; Baroni D et al. J. Bioenerg. Biomembr., 2013 Aug;45:353-68). This variant also disrupts a known characteristic residue of the domain indicated to be necessary for proper function of SCN1B (Wallace RH et al. Nat. Genet., 1998 Aug;19:366-70; Namadurai S et al. J. Biol. Chem., 2014 Apr;289:10797-811; McCormick KA et al. J. Biol. Chem., 1998 Feb;273:3954-62; Robertson SC et al. Proc. Natl. Acad. Sci. U.S.A., 1998 Apr;95:4567-72). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation for SCN1B-related epilepsy; however, the association of this alteration with SCN1B-related arrhythmia is unknown. (less)
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Not provided
Affected status: not provided
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280460.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Cys121Trp (c.363C>G) in SCN1B This variant has been described in association with generalized epilepsy with febrile seizures-plus (GEFS+) but has not been reported in association with familial cardiomyopathies. Wallace et al (1998) reported a large family with GEFS+ with linkage with a l od score of 3.85. They then identified the p.Cys121Trp variant in SCN1B at the linked locus and concluded it was the causative variant. Interestingly, a few children in the family who had febrile seizures did not have this variant. The authors considered these cases to be either phenocopies or genocopies. The same group reported another family with this variant, in which 13 of 14 family members studied with GEFS+ had the p.Cys121Trp variant (Wallace et al 2002). Four unaffected family members carried the variant and the penetrance was estimated at 76%. This family had a common haplotype with the previously reported family, suggesting they belong to the same kindred or there was a found effect. There is evidence that this variant leads to loss-of-function in terms of modulation of channel-gating kinetics (Wallace et al 1998; Tammaro et al 2002). The variant is expected to disrupt a putative disulfide bridge that normally maintains an extracellular immunoglobulin-like fold. Another group reported a family with febrile seizures-plus and early-onset absence epilepsy that had a different variant in SCN1B (Audenaert et al 2003). Five of six affected individuals had the IVS2-2A>C variant, which resulted in the use of an cryptic splice acceptor site and deletion of five amino acids. Variants in this gene are now thought to be a rare cause of GEFS+ (Wallace et al 2001, Wallace et al 2002, Audenaert et al 2003). Wallace et al (1998) did not observe the variant in 96 control individuals. It is not listed in dbSNP (as of March 3rd, 2011). (less)
Number of individuals with the variant: 2
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Pathogenic
(May 14, 2002)
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no assertion criteria provided
Method: literature only
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GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030055.5
First in ClinVar: Apr 04, 2013 Last updated: Nov 11, 2023 |
Comment on evidence:
In affected members of a large family, most of them living in the Australian state of Tasmania (Singh et al., 1999), with generalized epilepsy with … (more)
In affected members of a large family, most of them living in the Australian state of Tasmania (Singh et al., 1999), with generalized epilepsy with febrile seizures plus-1 (GEFSP1; 604233), Wallace et al. (1998) identified a heterozygous c.387C-G transversion in the SCN11B gene, resulting in a cys121-to-trp (C121W) substitution. The substitution occurred at a conserved residue in the putative disulfide bridge that normally maintains an extracellular immunoglobulin-like fold. Coexpression of mutant beta-1 subunit with a brain sodium channel alpha subunit in Xenopus laevis oocytes demonstrated that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. Tammaro et al. (2002) expressed wildtype rat beta-1 or mutant rat beta-1 with the C121W substitution in human embryonic kidney cells stably expressing the rat alpha subunit (SCN4A; 603967). Wildtype beta-1 increased the density of sodium channels on the cell surface and modulated the inactivation of the sodium current, hastening recovery from inactivation. In contrast, beta-1 with C121W lacked the ability to modulate sodium currents, but it maintained the ability to increase current density. Wallace et al. (2002) identified a second family, from Queensland, Australia, with GEFS+ and the C121W mutation. Of 19 individuals with seizures, 16 had phenotypes within the GEFS+ spectrum. The mutation was present in 13 of 14 individuals with GEFS+ available for testing and in 1 of the 3 individuals with seizures not consistent with the GEFS+ phenotype. Four unaffected members tested also carried the mutation. The penetrance of the mutation in this family was determined to be 76%. A common haplotype was observed in this family and the family reported by Wallace et al. (1998), suggesting a founder effect. Grinton et al. (2022) reported evidence of a single founder event giving rise to this variant in 14 unrelated families with the GEFS+ phenotype, which occurred about 800 years earlier. Grinton et al. (2022) stated that the nucleotide change in this variant is c.363C-G. (less)
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Pathogenic
(Oct 29, 2023)
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no assertion criteria provided
Method: clinical testing
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SCN1B-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004714492.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The SCN1B c.363C>G variant is predicted to result in the amino acid substitution p.Cys121Trp. This variant has been reported to segregate in multiple large families … (more)
The SCN1B c.363C>G variant is predicted to result in the amino acid substitution p.Cys121Trp. This variant has been reported to segregate in multiple large families with generalized epilepsy with febrile seizures plus (GEFS+) with incomplete penetrance (Wallace et al. 1998. PubMed ID: 9697698; Scheffer et al. 2006. PubMed ID: 17020904). In vitro functional studies demonstrate a deleterious effect on SCN1B function by failing to modulate the sodium channel inactivating ability appropriately (Wallace et al. 1998. PubMed ID: 9697698) and in vivo functional studies demonstrates that mice expressing this variant were more prone to heat-induced seizures, decreased SCN1B protein expression in the brain, and subcellular mislocalization when compared to mice expressing wild type SCN1B (Kruger et al. 2016. PubMed ID: 27277800). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-35524558-C-G) and has been reported in ClinVar as pathogenic and likely pathogenic by other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/9252/). This variant is interpreted as pathogenic. (less)
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Comment:
Comment:
Converted during submission to Pathogenic.
Comment:
This variant has been reported in the literature and in public databases in numerous individuals with generalized epilepsy with febrile seizures plus (GEFS+), and has been shown to segregate with GEFS+ in multiple large families, though it does appear to exhibit incomplete penetrance (Selected publications: Wallace 1998 PMID: 9697698; Scheffer 2007 PMID: 17020904; Butler 2017 PMID: 29056246; ClinVar Variation ID: 9252). However, this variant was also noted to not segregate with the febrile seizures phenotype in several individuals in one of the large families studied (Wallace 1998 PMID: 9697698). Of note, this variant has not been reported in association with cardiac arrhythmia. This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.003% [4/129198]; https://gnomad.broadinstitute.org/variant/19-35524558-C-G?dataset=gnomad_r2_1); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, incomplete penetrance, and/or variable expressivity. This variant is well characterized functionally, with in vitro studies demonstrating that this variant alters sodium channel activity, specifically temperature-dependent hyperexcitability (Selected publications: Wallace 1998 PMID: 9697698; Meadows 2002 PMID: 12486163; Tammaro 2002 PMID: 11866477; Egri 2012 PMID: 22292491). Mouse models with this variant were found to have increased susceptibility to hyperthermia-induced convulsions compared to those with the wild-type sodium channel (Kruger 2016 PMID: 27277800). This variant alters a cysteine residue that is involved in a disulfide bridge predicted to stabilize the extracellular immunoglobulin domain of the encoded protein (Wallace 1998 PMID: 9697698; Barbieri 2012 PMID: 22425777). Evolutionary conservation and computational predictive tools further support that this variant impacts the protein. In summary, this variant is classified as pathogenic.
Comment:
Published functional studies demonstrate altered channel function (Wallace et al., 1998; Meadows et al., 2002; Barbieri et al., 2012; Egri et al., 2012; Baroni et al., 2013; Kruger et al., 2016); Reported previously in an individual with late onset episodic ataxia; segregation analysis not performed (Maksemous et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 23584539, 9697698, 12011299, 27216889, 22425777, 11866477, 12486163, 22292491, 24065921, 23527921, 17020904, 28070485, 28488083, 28717674, 29056246, 29620010, 30921204, 29263209, 29992740, 29661262, 29307654, 29335582, 31709768, 31211177, 32303391, 33526774, 33301879, 33841294, 34583279, 31440721, 32466254, 36288729, 24623842, 27277800)
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 121 of the SCN1B protein (p.Cys121Trp). This variant is present in population databases (rs104894718, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant SCN1B-related conditions (PMID: 9697698, 12011299, 17020904). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9252). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN1B function (PMID: 20628201, 25421039, 27277800, 28331474). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.C121W pathogenic mutation (also known as c.363C>G), located in coding exon 3 of the SCN1B gene, results from a C to G substitution at nucleotide position 363. The cysteine at codon 121 is replaced by tryptophan, an amino acid with highly dissimilar properties. In three separate studies, with over 100 individuals tested, this alteration was shown to significantly segregate with disease with reduced penetrance (62-76%). In total, it was detected in 44 individuals with a variety of seizure types, including: febrile, generalized epilepsy with febrile seizures plus (GEFS+), afebrile, generalized tonic clonic, (GTC), absence, temporal lobe, and Dravet syndrome (Wallace RH et al. Nat. Genet., 1998 Aug;19:366-70; Wallace RH et al. Neurology, 2002 May;58:1426-9; Scheffer IE et al. Brain, 2007 Jan;130:100-9; Carvill GL et al. Neurology, 2014 Apr;82:1245-53). In addition, several in vitro and in vivo studies indicate that this alteration results in aberrant channel function, more specifically, thermal sensitive hyperexcitability (Barbieri R et al. Biochem. Biophys. Res. Commun., 2012 Apr;420:364-7; Meadows LS et al. J. Neurosci., 2002 Dec;22:10699-709; Tammaro P et al. Biochem. Biophys. Res. Commun., 2002 Mar;291:1095-101; Egri C et al. Epilepsia, 2012 Mar;53:494-505; Kruger LC et al. J. Neurosci., 2016 Jun;36:6213-24; Baroni D et al. J. Bioenerg. Biomembr., 2013 Aug;45:353-68). This variant also disrupts a known characteristic residue of the domain indicated to be necessary for proper function of SCN1B (Wallace RH et al. Nat. Genet., 1998 Aug;19:366-70; Namadurai S et al. J. Biol. Chem., 2014 Apr;289:10797-811; McCormick KA et al. J. Biol. Chem., 1998 Feb;273:3954-62; Robertson SC et al. Proc. Natl. Acad. Sci. U.S.A., 1998 Apr;95:4567-72). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation for SCN1B-related epilepsy; however, the association of this alteration with SCN1B-related arrhythmia is unknown.
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Cys121Trp (c.363C>G) in SCN1B This variant has been described in association with generalized epilepsy with febrile seizures-plus (GEFS+) but has not been reported in association with familial cardiomyopathies. Wallace et al (1998) reported a large family with GEFS+ with linkage with a l od score of 3.85. They then identified the p.Cys121Trp variant in SCN1B at the linked locus and concluded it was the causative variant. Interestingly, a few children in the family who had febrile seizures did not have this variant. The authors considered these cases to be either phenocopies or genocopies. The same group reported another family with this variant, in which 13 of 14 family members studied with GEFS+ had the p.Cys121Trp variant (Wallace et al 2002). Four unaffected family members carried the variant and the penetrance was estimated at 76%. This family had a common haplotype with the previously reported family, suggesting they belong to the same kindred or there was a found effect. There is evidence that this variant leads to loss-of-function in terms of modulation of channel-gating kinetics (Wallace et al 1998; Tammaro et al 2002). The variant is expected to disrupt a putative disulfide bridge that normally maintains an extracellular immunoglobulin-like fold. Another group reported a family with febrile seizures-plus and early-onset absence epilepsy that had a different variant in SCN1B (Audenaert et al 2003). Five of six affected individuals had the IVS2-2A>C variant, which resulted in the use of an cryptic splice acceptor site and deletion of five amino acids. Variants in this gene are now thought to be a rare cause of GEFS+ (Wallace et al 2001, Wallace et al 2002, Audenaert et al 2003). Wallace et al (1998) did not observe the variant in 96 control individuals. It is not listed in dbSNP (as of March 3rd, 2011).
Comment:
The SCN1B c.363C>G variant is predicted to result in the amino acid substitution p.Cys121Trp. This variant has been reported to segregate in multiple large families with generalized epilepsy with febrile seizures plus (GEFS+) with incomplete penetrance (Wallace et al. 1998. PubMed ID: 9697698; Scheffer et al. 2006. PubMed ID: 17020904). In vitro functional studies demonstrate a deleterious effect on SCN1B function by failing to modulate the sodium channel inactivating ability appropriately (Wallace et al. 1998. PubMed ID: 9697698) and in vivo functional studies demonstrates that mice expressing this variant were more prone to heat-induced seizures, decreased SCN1B protein expression in the brain, and subcellular mislocalization when compared to mice expressing wild type SCN1B (Kruger et al. 2016. PubMed ID: 27277800). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-35524558-C-G) and has been reported in ClinVar as pathogenic and likely pathogenic by other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/9252/). This variant is interpreted as pathogenic.
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:
The SCN1B c.363C>G (p.Cys121Trp) variant is a missense variant that has been reported in at least three studies in which it is identified in a heterozygous state in at least 45 individuals from several large multi-generation families with generalized epilepsy with febrile seizures plus (GEFS+) exhibiting a range of seizure types. Seizure types included febrile, febrile seizures plus, absence and generalized tonic clonic seizures, temporal lobe epilepsy, myoclonic-astatic epilepsy and unclassified seizures (Wallace et al. 1998; Wallace et al. 2002; Scheffer et al. 2007). The p.Cys121Trp variant is also found in a heterozygous state in multiple unaffected individuals supporting incomplete penetrance of up to 60% as noted by Wallace et al. (1998), or the presence of other factors that may modify the phenotype (Scheffer et al. 2007; Carvill et al. 2014). The p.Cys121Trp variant is reported at a frequency of 0.0000310 in the European (non-Finnish) population of the Genome Aggregation Database which may be consistent with reduced penetrance. The p.Cys121Trp variant affects a highly conserved cysteine residue and putatively disrupts a disulphide bridge in the extracellular domain of the protein that maintains the structure of an extracellular immunoglobulin-like fold. Functional studies in mice expressing the Scn1b-C121W (Scn1b+/W) allele compared to mice heterozygous for the Scn1b-null allele (Scn1b+/-) demonstrated the mice expressing the Scn1b+/W allele were more susceptible to hyperthermia-induced convulsions. The same study also demonstrated that the variant protein was expressed at lower levels in the brain (approximately 50% that of wild type) and may be incompletely glycosylated resulting in abnormal subcellular localization of the protein (Kruger et al. 2016). The variant is suggested to result in a deleterious gain-of-function (Kruger et al. 2016). Based on the collective evidence and application of the ACMG criteria, the p.Cys121Trp variant is classified as pathogenic for generalized epilepsy with febrile seizures plus.
Comment:
Converted during submission to Pathogenic.
Comment:
This variant has been reported in the literature and in public databases in numerous individuals with generalized epilepsy with febrile seizures plus (GEFS+), and has been shown to segregate with GEFS+ in multiple large families, though it does appear to exhibit incomplete penetrance (Selected publications: Wallace 1998 PMID: 9697698; Scheffer 2007 PMID: 17020904; Butler 2017 PMID: 29056246; ClinVar Variation ID: 9252). However, this variant was also noted to not segregate with the febrile seizures phenotype in several individuals in one of the large families studied (Wallace 1998 PMID: 9697698). Of note, this variant has not been reported in association with cardiac arrhythmia. This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.003% [4/129198]; https://gnomad.broadinstitute.org/variant/19-35524558-C-G?dataset=gnomad_r2_1); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, incomplete penetrance, and/or variable expressivity. This variant is well characterized functionally, with in vitro studies demonstrating that this variant alters sodium channel activity, specifically temperature-dependent hyperexcitability (Selected publications: Wallace 1998 PMID: 9697698; Meadows 2002 PMID: 12486163; Tammaro 2002 PMID: 11866477; Egri 2012 PMID: 22292491). Mouse models with this variant were found to have increased susceptibility to hyperthermia-induced convulsions compared to those with the wild-type sodium channel (Kruger 2016 PMID: 27277800). This variant alters a cysteine residue that is involved in a disulfide bridge predicted to stabilize the extracellular immunoglobulin domain of the encoded protein (Wallace 1998 PMID: 9697698; Barbieri 2012 PMID: 22425777). Evolutionary conservation and computational predictive tools further support that this variant impacts the protein. In summary, this variant is classified as pathogenic.
Comment:
Published functional studies demonstrate altered channel function (Wallace et al., 1998; Meadows et al., 2002; Barbieri et al., 2012; Egri et al., 2012; Baroni et al., 2013; Kruger et al., 2016); Reported previously in an individual with late onset episodic ataxia; segregation analysis not performed (Maksemous et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 23584539, 9697698, 12011299, 27216889, 22425777, 11866477, 12486163, 22292491, 24065921, 23527921, 17020904, 28070485, 28488083, 28717674, 29056246, 29620010, 30921204, 29263209, 29992740, 29661262, 29307654, 29335582, 31709768, 31211177, 32303391, 33526774, 33301879, 33841294, 34583279, 31440721, 32466254, 36288729, 24623842, 27277800)
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 121 of the SCN1B protein (p.Cys121Trp). This variant is present in population databases (rs104894718, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant SCN1B-related conditions (PMID: 9697698, 12011299, 17020904). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9252). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN1B function (PMID: 20628201, 25421039, 27277800, 28331474). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.C121W pathogenic mutation (also known as c.363C>G), located in coding exon 3 of the SCN1B gene, results from a C to G substitution at nucleotide position 363. The cysteine at codon 121 is replaced by tryptophan, an amino acid with highly dissimilar properties. In three separate studies, with over 100 individuals tested, this alteration was shown to significantly segregate with disease with reduced penetrance (62-76%). In total, it was detected in 44 individuals with a variety of seizure types, including: febrile, generalized epilepsy with febrile seizures plus (GEFS+), afebrile, generalized tonic clonic, (GTC), absence, temporal lobe, and Dravet syndrome (Wallace RH et al. Nat. Genet., 1998 Aug;19:366-70; Wallace RH et al. Neurology, 2002 May;58:1426-9; Scheffer IE et al. Brain, 2007 Jan;130:100-9; Carvill GL et al. Neurology, 2014 Apr;82:1245-53). In addition, several in vitro and in vivo studies indicate that this alteration results in aberrant channel function, more specifically, thermal sensitive hyperexcitability (Barbieri R et al. Biochem. Biophys. Res. Commun., 2012 Apr;420:364-7; Meadows LS et al. J. Neurosci., 2002 Dec;22:10699-709; Tammaro P et al. Biochem. Biophys. Res. Commun., 2002 Mar;291:1095-101; Egri C et al. Epilepsia, 2012 Mar;53:494-505; Kruger LC et al. J. Neurosci., 2016 Jun;36:6213-24; Baroni D et al. J. Bioenerg. Biomembr., 2013 Aug;45:353-68). This variant also disrupts a known characteristic residue of the domain indicated to be necessary for proper function of SCN1B (Wallace RH et al. Nat. Genet., 1998 Aug;19:366-70; Namadurai S et al. J. Biol. Chem., 2014 Apr;289:10797-811; McCormick KA et al. J. Biol. Chem., 1998 Feb;273:3954-62; Robertson SC et al. Proc. Natl. Acad. Sci. U.S.A., 1998 Apr;95:4567-72). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation for SCN1B-related epilepsy; however, the association of this alteration with SCN1B-related arrhythmia is unknown.
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Cys121Trp (c.363C>G) in SCN1B This variant has been described in association with generalized epilepsy with febrile seizures-plus (GEFS+) but has not been reported in association with familial cardiomyopathies. Wallace et al (1998) reported a large family with GEFS+ with linkage with a l od score of 3.85. They then identified the p.Cys121Trp variant in SCN1B at the linked locus and concluded it was the causative variant. Interestingly, a few children in the family who had febrile seizures did not have this variant. The authors considered these cases to be either phenocopies or genocopies. The same group reported another family with this variant, in which 13 of 14 family members studied with GEFS+ had the p.Cys121Trp variant (Wallace et al 2002). Four unaffected family members carried the variant and the penetrance was estimated at 76%. This family had a common haplotype with the previously reported family, suggesting they belong to the same kindred or there was a found effect. There is evidence that this variant leads to loss-of-function in terms of modulation of channel-gating kinetics (Wallace et al 1998; Tammaro et al 2002). The variant is expected to disrupt a putative disulfide bridge that normally maintains an extracellular immunoglobulin-like fold. Another group reported a family with febrile seizures-plus and early-onset absence epilepsy that had a different variant in SCN1B (Audenaert et al 2003). Five of six affected individuals had the IVS2-2A>C variant, which resulted in the use of an cryptic splice acceptor site and deletion of five amino acids. Variants in this gene are now thought to be a rare cause of GEFS+ (Wallace et al 2001, Wallace et al 2002, Audenaert et al 2003). Wallace et al (1998) did not observe the variant in 96 control individuals. It is not listed in dbSNP (as of March 3rd, 2011).
Comment:
The SCN1B c.363C>G variant is predicted to result in the amino acid substitution p.Cys121Trp. This variant has been reported to segregate in multiple large families with generalized epilepsy with febrile seizures plus (GEFS+) with incomplete penetrance (Wallace et al. 1998. PubMed ID: 9697698; Scheffer et al. 2006. PubMed ID: 17020904). In vitro functional studies demonstrate a deleterious effect on SCN1B function by failing to modulate the sodium channel inactivating ability appropriately (Wallace et al. 1998. PubMed ID: 9697698) and in vivo functional studies demonstrates that mice expressing this variant were more prone to heat-induced seizures, decreased SCN1B protein expression in the brain, and subcellular mislocalization when compared to mice expressing wild type SCN1B (Kruger et al. 2016. PubMed ID: 27277800). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-35524558-C-G) and has been reported in ClinVar as pathogenic and likely pathogenic by other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/9252/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure. | Grinton BE | American journal of human genetics | 2022 | PMID: 36288729 |
| Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia. | Maksemous N | Biomedicines | 2020 | PMID: 32466254 |
| Diagnostic Yield From 339 Epilepsy Patients Screened on a Clinical Gene Panel. | Butler KM | Pediatric neurology | 2017 | PMID: 29056246 |
| ExACtly zero or once: A clinically helpful guide to assessing genetic variants in mild epilepsies. | Bennett CA | Neurology. Genetics | 2017 | PMID: 28717674 |
| Sodium Channel β Subunits in Epilepsy: Location, Location, Location. | Kearney JA | Epilepsy currents | 2017 | PMID: 28331474 |
| β1-C121W Is Down But Not Out: Epilepsy-Associated Scn1b-C121W Results in a Deleterious Gain-of-Function. | Kruger LC | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2016 | PMID: 27277800 |
| Structure-based site-directed photo-crosslinking analyses of multimeric cell-adhesive interactions of voltage-gated sodium channel β subunits. | Shimizu H | Scientific reports | 2016 | PMID: 27216889 |
| Differential gene expression profiles of two excitable rat cell lines after over-expression of WT- and C121W-β1 sodium channel subunits. | Baroni D | Neuroscience | 2015 | PMID: 25827112 |
| Sodium channel β1 subunit localizes to axon initial segments of excitatory and inhibitory neurons and shows regional heterogeneity in mouse brain. | Wimmer VC | The Journal of comparative neurology | 2015 | PMID: 25421039 |
| Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome. | Reid CA | Brain : a journal of neurology | 2014 | PMID: 24747835 |
| GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. | Carvill GL | Neurology | 2014 | PMID: 24623842 |
| Enhanced in vitro CA1 network activity in a sodium channel β1(C121W) subunit model of genetic epilepsy. | Hatch RJ | Epilepsia | 2014 | PMID: 24605816 |
| Crystal structure and molecular imaging of the Nav channel β3 subunit indicates a trimeric assembly. | Namadurai S | The Journal of biological chemistry | 2014 | PMID: 24567321 |
| A thermosensitive mutation alters the effects of lacosamide on slow inactivation in neuronal voltage-gated sodium channels, NaV1.2. | Abdelsayed M | Frontiers in pharmacology | 2013 | PMID: 24065921 |
| Functional modulation of voltage-dependent sodium channel expression by wild type and mutated C121W-β1 subunit. | Baroni D | Journal of bioenergetics and biomembranes | 2013 | PMID: 23584539 |
| Presence of epilepsy-associated variants in large exome databases. | Cherepanova NS | Journal of neurogenetics | 2013 | PMID: 23527921 |
| Identification of an intra-molecular disulfide bond in the sodium channel β1-subunit. | Barbieri R | Biochemical and biophysical research communications | 2012 | PMID: 22425777 |
| A thermoprotective role of the sodium channel β1 subunit is lost with the β1 (C121W) mutation. | Egri C | Epilepsia | 2012 | PMID: 22292491 |
| Voltage-gated Na+ channel β1B: a secreted cell adhesion molecule involved in human epilepsy. | Patino GA | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2011 | PMID: 21994374 |
| Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus. | Wimmer VC | The Journal of clinical investigation | 2010 | PMID: 20628201 |
| Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. | Dibbens LM | Annals of neurology | 2010 | PMID: 20437590 |
| Slow inactivation of the NaV1.4 sodium channel in mammalian cells is impeded by co-expression of the beta1 subunit. | Webb J | Pflugers Archiv : European journal of physiology | 2009 | PMID: 18941776 |
| Modulatory proteins can rescue a trafficking defective epileptogenic Nav1.1 Na+ channel mutant. | Rusconi R | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2007 | PMID: 17928445 |
| Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. | Scheffer IE | Brain : a journal of neurology | 2007 | PMID: 17020904 |
| Lack of an association between candidate gene loci and idiopathic generalized epilepsy in Kuwaiti Arab children. | Haider MZ | Journal of biomedical science | 2005 | PMID: 16205844 |
| Mutation in the Na+ channel subunit SCN1B produces paradoxical changes in peripheral nerve excitability. | Kiernan MC | Brain : a journal of neurology | 2005 | PMID: 15857929 |
| Hemojuvelin (HJV)-associated hemochromatosis: analysis of HJV and HFE mutations and iron overload in three families. | Wallace DF | Haematologica | 2005 | PMID: 15710580 |
| Membrane proteins with immunoglobulin-like domains--a master superfamily of interaction molecules. | Barclay AN | Seminars in immunology | 2003 | PMID: 14690046 |
| A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. | Audenaert D | Neurology | 2003 | PMID: 14504340 |
| Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1. | Meadows LS | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2002 | PMID: 12486163 |
| Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B. | Wallace RH | Neurology | 2002 | PMID: 12011299 |
| Modulation of sodium current in mammalian cells by an epilepsy-correlated beta 1-subunit mutation. | Tammaro P | Biochemical and biophysical research communications | 2002 | PMID: 11866477 |
| Skeletal muscle sodium channel is affected by an epileptogenic beta1 subunit mutation. | Moran O | Biochemical and biophysical research communications | 2001 | PMID: 11263970 |
| Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. | Wallace RH | American journal of human genetics | 2001 | PMID: 11254444 |
| Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. | Singh R | Annals of neurology | 1999 | PMID: 9894880 |
| Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. | Wallace RH | Nature genetics | 1998 | PMID: 9697698 |
| Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain. | Robertson SC | Proceedings of the National Academy of Sciences of the United States of America | 1998 | PMID: 9539778 |
| Molecular determinants of Na+ channel function in the extracellular domain of the beta1 subunit. | McCormick KA | The Journal of biological chemistry | 1998 | PMID: 9461582 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN1B | - | - | - | - |
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Text-mined citations for rs104894718 ...
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Record last updated Nov 03, 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.