ClinVar Genomic variation as it relates to human health

The p.R85C variant (also known as c.253C>T), located in coding exon 3 of the SCN1B gene, results from a C to T substitution at nucleotide position 253. The arginine at codon 85 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported to segregate with disease in a family with multiple individuals across generations affected with seizure disorders, ranging from isolated febrile seizures through generalized epilepsy with febrile seizures plus (GEFS+); however, no cardiac clinical information was provided (Scheffer IE et al. Brain, 2007 Jan;130:100-9). This variant has been reported to segregate with disease in a second family with multiple heterozygous individuals affected with febrile seizures and one homozygous individual affected with an early infantile developmental and epileptic encephalopathy (EIDEE) and no detected cardiac arrhythmias (Aeby A et al. Ann Clin Transl Neurol, 2019 12;6:2354-2367). Functional studies have demonstrated that this variant, as well as close match p.R85H, fails to properly regulate the electrophysiological properties of sodium channels (Xu R et al. Neuroscience, 2007 Aug;148:164-74). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is likely pathogenic for autosomal dominant SCN1B-related epilepsy with febrile seizures; however, the association of this alteration with autosomal recessive early infantile epileptic encephalopathy and autosomal dominant Brugada syndrome is uncertain.

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.

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.

The missense c.253C>T(p.Arg85Cys) variant in SCN1B gene has been reported in heterozygous state in multiple individuals affected with SCN1B related disorders (Aeby A, et. al., 2019). Experimental studies have shown that this missense change affects SCN1B function (Xu R, et. al., 2007). The p.Arg85Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance/Pathogenic/Likely pathogenic. The amino acid change p.Arg85Cys in SCN1B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 85 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 85 of the SCN1B protein (p.Arg85Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+) and autosomal recessive epileptic encephalopathy with cerebellar atrophy (PMID: 17020904, 31709768; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190859). 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: 17629415, 31709768). 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. For these reasons, this variant has been classified as Pathogenic.