ClinVar Miner

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

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Total submissions: 5
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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 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.
Illumina Clinical Services Laboratory,Illumina RCV001127219 SCV001286510 uncertain significance Brugada syndrome 5 2017-10-16 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV001127219 SCV001407089 likely pathogenic Brugada syndrome 5 2019-09-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 85 of the SCN1B protein (p.Arg85Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with generalized epilepsy with febrile seizures plus (GEFS+) in a family (PMID: 17020904). ClinVar contains an entry for this variant (Variation ID: 190859). This variant has been reported to affect SCN1B protein function (PMID: 17629415). This variant disrupts the p.Arg85 amino acid residue in SCN1B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17020904, 17629415, 19808477). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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