19-35033654-C-G
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_001037.5(SCN1B):āc.363C>Gā(p.Cys121Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.00011 ( 0 hom. )
Consequence
SCN1B
NM_001037.5 missense
NM_001037.5 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 1.99
Genes affected
SCN1B (HGNC:10586): (sodium voltage-gated channel beta subunit 1) Voltage-gated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells. They are composed of one alpha and two beta subunits, where the alpha subunit provides channel activity and the beta-1 subunit modulates the kinetics of channel inactivation. This gene encodes a sodium channel beta-1 subunit. Mutations in this gene result in generalized epilepsy with febrile seizures plus, Brugada syndrome 5, and defects in cardiac conduction. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a disulfide_bond (size 81) in uniprot entity SCN1B_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001037.5
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
Variant 19-35033654-C-G is Pathogenic according to our data. Variant chr19-35033654-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35033654-C-G is described in Lovd as [Pathogenic]. Variant chr19-35033654-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SCN1B | NM_001037.5 | c.363C>G | p.Cys121Trp | missense_variant | 3/6 | ENST00000262631.11 | NP_001028.1 | |
| SCN1B | NM_199037.5 | c.363C>G | p.Cys121Trp | missense_variant | 3/3 | NP_950238.1 | ||
| SCN1B | NM_001321605.2 | c.264C>G | p.Cys88Trp | missense_variant | 3/6 | NP_001308534.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN1B | ENST00000262631.11 | c.363C>G | p.Cys121Trp | missense_variant | 3/6 | 1 | NM_001037.5 | ENSP00000262631.3 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251490Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
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GnomAD4 exome AF: 0.000113 AC: 165AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 88AN XY: 727248
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GnomAD4 genome 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74342
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
| Likely pathogenic, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | - | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 11, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2023 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 31, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 28, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 29, 2016 | - - |
Generalized epilepsy with febrile seizures plus, type 1 Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 25, 2024 | Criteria applied: PS4,PS3_MOD,PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 25, 2016 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 14, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with generalised epilepsy with febrile seizures plus, type 1 (GEFS+: MIM#604233) and developmental and epileptic encephalopathy 52 (MIM#617350). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene has been reported to be associated with both autosomal recessive and autosomal dominant epilepsy (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. The disease penetrance of the p.(Cys121Trp) variant for GEFS+ is found to be 62ā76% (PMID: 36291443). (I) 0115 - Variants in this gene are known to have variable expressivity. Families with SCN1B-related epilepsy may have members with that same variant that are seizure-free, have febrile seizures or have epilepsy (most frequently FS+) (PMID: 36291443). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3: 4 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by clinical laboratories in ClinVar and reported in individuals with autosomal dominant generalised epilepsy with febrile seizures plus (PMID: 17020904, PMID: 12011299). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant was shown to segregate in three families with autosomal dominant generalised epilepsy with febrile seizures plus (PMID: 17020904, PMID: 12011299). (SP) 1206 - This variant has been shown to be paternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 16, 2021 | 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. - |
Generalized epilepsy with febrile seizures plus, type 1;C2748541:Brugada syndrome 5;C3809311:Atrial fibrillation, familial, 13;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 10, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Sep 01, 2022 | 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. - |
Brugada syndrome 5 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | 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. - |
Generalized epilepsy with febrile seizures plus Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Atrial fibrillation, familial, 13 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Dec 17, 2014 | - - |
SCN1B-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 29, 2023 | 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. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2022 | 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. - |
Computational scores
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AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;.;.
Sift4G
Pathogenic
D;.;D;.;.
Polyphen
D;D;D;.;.
Vest4
MVP
MPC
2.0
ClinPred
D
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RBP_binding_hub_radar
RBP_regulation_power_radar
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at