ClinVar Miner

Submissions for variant NM_001037.5(SCN1B):c.457G>A (p.Asp153Asn)

gnomAD frequency: 0.00009  dbSNP: rs72550247
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766769 SCV000223628 uncertain significance not provided 2022-11-04 criteria provided, single submitter clinical testing Initially published as a pathogenic variant in an individual with atrial fibrillation, and functional studies show that D153N results in loss of function of the protein (Watanabe et al., 2009); however, as seizures were not reported in the affected individual, the association of D153N with epilepsy, if any, is unknown; Reported previously in two individuals in a large population cohort who had exome sequencing; the authors classified D153N as a variant of unknown significance (Dorschner et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Garde2020[CaseControl], 27435932, 24055113, 19808477, 21682648, 23838598, 34867379)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000171064 SCV000540269 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with no segregations. In vitro functional study suggests variant results in loss of function; ClinVar: VUS by GeneDx
Ambry Genetics RCV000620098 SCV000737774 uncertain significance Cardiovascular phenotype 2021-11-12 criteria provided, single submitter clinical testing The p.D153N variant (also known as c.457G>A), located in coding exon 4 of the SCN1B gene, results from a G to A substitution at nucleotide position 457. The aspartic acid at codon 153 is replaced by asparagine, an amino acid with highly similar properties. This variant has been described in an atrial fibrillation cohort with limited genes analyzed, and functional analyses suggested possible impact (Watanabe H et al. Circ Arrhythm Electrophysiol. 2009;2(3):268-75). In another study, this variant was detected in conjunction with other alterations in cardiovascular-related genes in a case of sudden unexplained death (Methner DN et al. Genome Res. 2016;26(9):1170-7). This variant was also reported as an incidental finding from 2 of 1000 participants' exomes and was classified as a variant of unknown significance (VUS) (Dorschner MO et al. Am J Hum Genet. 2013;93:631-40). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, the clinical significance of this variant for Brugada syndrome and autosomal recessive SCN1B-related early infantile epileptic encephalopathy is unclear; however, due to its observed frequencies in various cohorts, this variant is unlikely to be causative of autosomal dominant SCN1B-related epilepsy.
Invitae RCV001853079 SCV002159046 uncertain significance Brugada syndrome 5 2023-12-22 criteria provided, single submitter clinical testing The SCN1B gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001037.5, and corresponds to NM_199037.4:c.*5027G>A in the primary transcript. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 153 of the SCN1B protein (p.Asp153Asn). This variant is present in population databases (rs72550247, gnomAD 0.02%). This missense change has been observed in individual(s) with atrial fibrillation or sudden death (PMID: 19808477, 27435932). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects SCN1B function (PMID: 19808477). 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.
Fulgent Genetics, Fulgent Genetics RCV002477176 SCV002792224 uncertain significance Generalized epilepsy with febrile seizures plus, type 1; Brugada syndrome 5; Atrial fibrillation, familial, 13; Developmental and epileptic encephalopathy, 52 2021-09-22 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000766769 SCV003820754 uncertain significance not provided 2020-10-13 criteria provided, single submitter clinical testing
OMIM RCV000054538 SCV000083016 pathogenic Atrial fibrillation, familial, 13 2009-06-01 no assertion criteria provided literature only
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences RCV000234993 SCV000263120 pathogenic Death in early adulthood 2015-03-27 no assertion criteria provided clinical testing NM_001037.4:c.457G>A is pathogenic for Death in early adulthood in combination with NM_198056.2:c.1844G>A

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