ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720732 SCV000851613 pathogenic Seizures 2017-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Structural Evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Athena Diagnostics Inc RCV000171041 SCV000615050 pathogenic not provided 2016-12-31 criteria provided, single submitter clinical testing
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
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
GeneDx RCV000171041 SCV000223605 likely pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the SCN1B gene. The C121W variant in the SCN1B gene has been identified in several large families with genetic (generalized) epilepsy with febrile seizures plus (GEFS+), as well as multiple other seizure phenotypes (Wallace et al., 1998; Wallace et al., 2002; Scheffer et al., 2007). However, unaffected individuals harboring the C121W variant have also been reported, indicating lack of segregation with seizures, or incomplete penetrance and suggesting other factors may modify the phenotype (Scheffer et al., 2007; Carvill et al., 2014). The C121W variant is observed in 4/126712 (0.003%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The C121W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in vitro studies indicate that it results in 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).
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
Integrated Genetics/Laboratory Corporation of America RCV000030434 SCV000053103 pathogenic Generalized epilepsy with febrile seizures plus 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000646741 SCV000768526 pathogenic Brugada syndrome 5 2018-08-14 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 mice have shown that this 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.
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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