ClinVar Miner

Submissions for variant NM_001037.5(SCN1B):c.363C>G (p.Cys121Trp) (rs104894718)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030434 SCV000053103 pathogenic Generalized epilepsy with febrile seizures plus 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
GeneDx RCV000171041 SCV000223605 likely pathogenic not provided 2021-03-23 criteria provided, single submitter clinical testing Identified in several large families with generalized epilepsy with febrile seizures plus (GEFS+) and multiple other seizure phenotypes; however, unaffected individuals harboring the variant have also been reported, indicating lack of segregation with seizures, incomplete penetrance, and/or suggesting presence of other modifying factors (Wallace et al., 1998; Wallace et al., 2002; Scheffer et al., 2007; Carvill et al., 2014) Reported previously in an individual with late onset episodic ataxia; segregation analysis not performed (Maksemous et al., 2020) 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) Not observed at a significant frequency in large population cohorts (Lek et al., 2016) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000184010 SCV000236524 pathogenic Atrial fibrillation, familial, 13 2014-12-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000171041 SCV000340270 pathogenic not provided 2016-03-29 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000009834 SCV000596954 pathogenic Generalized epilepsy with febrile seizures plus, type 1 2016-08-25 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000171041 SCV000615050 pathogenic not provided 2016-12-31 criteria provided, single submitter clinical testing
Invitae RCV000646741 SCV000768526 pathogenic Brugada syndrome 5 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 121 of the SCN1B protein (p.Cys121Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is present in population databases (rs104894718, ExAC 0.001%). This variant has been reported to segregate with epilepsy in several large families (PMID: 9697698, 12011299, 17020904). ClinVar contains an entry for this variant (Variation ID: 9252). Experimental studies on mice have shown that a knock-in of this missense change recapitulates the human disease phenotype (PMID: 206282012, 5421039, 27277800, 28331474). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000720732 SCV000851613 pathogenic Seizures 2017-03-23 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV000763042 SCV000893521 likely pathogenic Generalized epilepsy with febrile seizures plus, type 1; Brugada syndrome 5; Atrial fibrillation, familial, 13; Epileptic encephalopathy, early infantile, 52 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000009834 SCV001786600 pathogenic Generalized epilepsy with febrile seizures plus, type 1 2021-02-16 criteria provided, single submitter clinical testing 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.
OMIM RCV000009834 SCV000030055 pathogenic Generalized epilepsy with febrile seizures plus, type 1 2002-05-14 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000171041 SCV000280460 likely pathogenic not provided no assertion criteria provided clinical testing 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).

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