Submissions for variant NM_001037.5(SCN1B):c.287G>A (p.Arg96Gln)

gnomAD frequency: 0.00002  dbSNP: rs372289648

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001123150	SCV001281959	uncertain significance	Generalized epilepsy with febrile seizures plus, type 1	2017-04-27	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.
Illumina Laboratory Services, Illumina	RCV001123151	SCV001281960	benign	Brugada syndrome 5	2017-04-27	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV001560471	SCV001782889	uncertain significance	not provided	2020-08-19	criteria provided, single submitter	clinical testing	Previously reported in one individual with sudden cardiac death who was diagnosed with hypertrophic cardiomyopathy on autopsy; however, this individual was also found to harbor a second cardiogenetic variant in a different gene, and no segregation data or additional clinical information was provided (Hertz et al., 2015; Previously reported in an individual with sudden unexpected death in epilepsy and no reported cardiac phenotype (Bagnall et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32651551, 26383259, 26704558)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001123151	SCV002189544	uncertain significance	Brugada syndrome 5	2024-07-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 96 of the SCN1B protein (p.Arg96Gln). This variant is present in population databases (rs372289648, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of SCN1B-related conditions (PMID: 26704558, 32651551). ClinVar contains an entry for this variant (Variation ID: 889314). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004032245	SCV005037146	uncertain significance	Cardiovascular phenotype	2023-11-13	criteria provided, single submitter	clinical testing	The p.R96Q variant (also known as c.287G>A), located in coding exon 3 of the SCN1B gene, results from a G to A substitution at nucleotide position 287. The arginine at codon 96 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in an individual from a sudden death in epilepsy cohort; however, details were limited (Bagnall RD et al. Ann Neurol, 2016 Apr;79:522-34). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for an autosomal dominant SCN1B-related epilepsy or Brugada syndrome-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant SCN1B-related epilepsy or Brugada syndrome; however, its contribution to the development of autosomal recessive SCN1B-related developmental and epileptic encephalopathy is uncertain.