Submissions for variant NM_001037.5(SCN1B):c.73G>A (p.Asp25Asn)

gnomAD frequency: 0.00001  dbSNP: rs786205837

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000171059	SCV000223623	pathogenic	not provided	2012-02-17	criteria provided, single submitter	clinical testing	p.Asp25Asn (GAC>AAC): c.73 G>A in the SCN1B gene. The Asp25Asn missense mutation in the SCN1B gene was previously reported as a de novo mutation in a patient who presented with a partial epileptic crisis (Orrico et al., 2009), and the NHLBI ESP Exome Variant Project did not identify Asp25Asn in approximately 5000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Asp25Asn results in a non-conservative amino acid substitution, as a negatively charged Aspartic acid residue is replaced by an uncharged Asparagine residue. It alters a highly conserved position in the N-terminal region of the voltage-gated sodium channel protein Navß1, and a mutation at a neighboring codon (Leu28Ile) has been published in association with epilepsy (Klassen et al., 2011). The variant is found in EPILEPSY panel(s).
Ambry Genetics	RCV004020041	SCV001444701	uncertain significance	Cardiovascular phenotype	2023-03-18	criteria provided, single submitter	clinical testing	The p.D25N variant (also known as c.73G>A), located in coding exon 2 of the SCN1B gene, results from a G to A substitution at nucleotide position 73. The aspartic acid at codon 25 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in a subject with epilepsy and has been reported in an epilepsy genetic testing cohort (Orrico A et al. Clin Genet, 2009 Jun;75:579-81; Lindy AS et al. Epilepsia, 2018 May;59:1062-1071). This alteration may have an impact on protein function (Baroni D et al. Hum Mutat, 2018 Oct;39:1402-1415). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517646	SCV003443902	uncertain significance	Brugada syndrome 5	2022-04-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 25 of the SCN1B protein (p.Asp25Asn). This variant is present in population databases (rs786205837, gnomAD 0.01%). This missense change has been observed in individual(s) with SCN1B-related conditions (PMID: 19522081). ClinVar contains an entry for this variant (Variation ID: 190879). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects SCN1B function (PMID: 29992740). 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.