ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs16969925
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Total submissions: 5
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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.
OMIM RCV000054537 SCV000083015 pathogenic Atrial fibrillation, familial, 13 2009-06-01 no assertion criteria provided literature only

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