ClinVar Miner

Submissions for variant NM_001037.5(SCN1B):c.253C>T (p.Arg85Cys) (rs786205830)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000500892 SCV000596955 likely pathogenic Generalized epilepsy with febrile seizures plus, type 1 2016-12-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620273 SCV000737877 likely pathogenic Cardiovascular phenotype 2017-01-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Good segregation with disease (lod 1.5-3 = 5-9 meioses),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Well-characterized mutation at same position
Illumina Clinical Services Laboratory,Illumina RCV000500892 SCV000915824 uncertain significance Generalized epilepsy with febrile seizures plus, type 1 2017-10-19 criteria provided, single submitter clinical testing The SCN1B c.253C>T (p.Arg85Cys) variant has been reported in a single study and identified in a heterozygous state in four related individuals, including three with generalized epilepsy with febrile seizures plus (GEFS+) and one with febrile seizures (Scheffer et al. 2007). This family had 20 individuals over five generations reported to be affected with seizure disorder; however, the majority were not available to be screened for the variant. One unaffected family member had children and grandchildren with phenotypes consistent with GEFS+, but did not carry the variant. The p.Arg85Cys variant was absent from 96 controls and is not reported in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Functional studies were performed using HEK-293 cells and found that the variant shifts steady state, fast and slow inactivation in the negative direction and was more excitable than wild type with low current injections (Thomas et al. 2007; Xu et al. 2007). Thomas et al. (2007) also observed partial excitability modulating properties. Based on the evidence, the p.Arg85Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for generalized epilepsy with febrile seizures plus. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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