Submissions for variant NM_001037.5(SCN1B):c.254G>A (p.Arg85His)

gnomAD frequency: 0.00002  dbSNP: rs16969925

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485749	SCV000568234	pathogenic	not provided	2020-03-31	criteria provided, single submitter	clinical testing	Identified in an individual with atrial fibrillation who had no neurological phenotype (Watanabe et al., 2009); Published functional studies demonstrate a damaging effect as this variant results in a loss-of-function of the resultant channel protein (Xu et al., 2007; Watanabe et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17604911, 17629415, 19710327, 27216889, 17020904, 19808477, 23838598, 28717674, 31465153, 31980526)
Fulgent Genetics, Fulgent Genetics	RCV000763041	SCV000893520	pathogenic	Generalized epilepsy with febrile seizures plus, type 1; Brugada syndrome 5; Atrial fibrillation, familial, 13; Developmental and epileptic encephalopathy, 52	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001059134	SCV001223745	pathogenic	Brugada syndrome 5	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 85 of the SCN1B protein (p.Arg85His). This variant is present in population databases (rs16969925, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of generalized epilepsy with febrile seizures plus (GEFS+) (PMID: 17020904). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60767). 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, 19808477). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002453365	SCV002740132	likely pathogenic	Cardiovascular phenotype	2023-03-09	criteria provided, single submitter	clinical testing	The p.R85H variant (also known as c.254G>A), located in coding exon 3 of the SCN1B gene, results from a G to A substitution at nucleotide position 254. The arginine at codon 85 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in an individual with atrial fibrillation (Watanabe H et al. Circ Arrhythm Electrophysiol, 2009 Jun;2:268-75). This variant has also been reported in two families and multiple individuals with presentations ranging from isolated febrile seizures to generalized epilepsy febrile seizures plus (GEFS+) and cardiac anomalies (Scheffer IE et al. Brain, 2007 Jan;130:100-9; Huo YC et al. Proc Natl Acad Sci, 2020 Feb;117:3053-3062; personal communications). Additionally, this alteration was observed in the homozygous state in an individual with seizure phenotype; however, cardiac clinical information was not provided (Ganapathy A. et al. Neurol. 2019 Aug;266(8):1919-1926). Another variant affecting this codon (p.R85C, c.253C>T) has been reported in association with seizure phenotype (Scheffer IE et al. Brain, 2007 Jan;130:100-9). Functional studies have suggested this variant may impact sodium channel function; however, the physiological relevance of the reported findings is unclear (Xu R et al. Neuroscience, 2007 Aug;148:164-74; Watanabe H et al. Circ Arrhythm Electrophysiol. 2009 Jun;2(3):268-75; Patino GA et al. J Neurosci, 2011 Oct;31:14577-91; Shimizu H et al. Sci Rep, 2016 May;6:26618). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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.
PreventionGenetics, part of Exact Sciences	RCV003974938	SCV004793644	pathogenic	SCN1B-related condition	2023-10-24	criteria provided, single submitter	clinical testing	The SCN1B c.254G>A variant is predicted to result in the amino acid substitution p.Arg85His. This variant has been reported in the heterozygous state in at least two individuals with generalized epilepsy with febrile seizures plus (GEFS+) (Scheffer et al. 2007. PubMed ID: 17020904; Bayat et al. 2022. PubMed ID: 35723786) and one individual with atrial fibrillation and aortic stenosis without a history of seizures (Watanabe et al. 2009. PubMed ID: 19808477). It has also been reported in the homozygous state in an individual with Dravet syndrome (Ganapathy et al. 2019. PubMed ID: 31069529). Moreover, this variant was shown to strongly co-segregate with disease in at least one family (Scheffer et al. 2007. PubMed ID: 17020904) and reportedly arose de novo in another (Bayat et al. 2022. PubMed ID: 35723786). Multiple in vitro studies have demonstrated that this variant negatively impacts the ability of the SCN1B protein to modulate the function of sodium channel proteins expressed in brain and cardiac tissue (Xu et al. 2007. PubMed ID: 1762941; Watanabe et al. 2009. PubMed ID: 19808477) and disrupts SCN1B-mediated cell adhesion (Shimizu et al. 2016. PubMed ID: 27216889). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-35524449-G-A). Of note, another missense variant at the same amino acid position (p.Arg85Cys) has been reported as pathogenic in GEFS+ patients with functional impacts similar to the p.Arg85His variant (Scheffer et al. 2007. PubMed ID: 17020904; Xu et al. 2007. PubMed ID: 17629415). Taken together, the p.Arg85His variant is interpreted as pathogenic.
OMIM	RCV000054537	SCV000083015	pathogenic	Atrial fibrillation, familial, 13	2009-06-01	no assertion criteria provided	literature only