Submissions for variant NM_001165963.4(SCN1A):c.2552A>G (p.Asn851Ser)

gnomAD frequency: 0.00002  dbSNP: rs561912072

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188891	SCV000242521	uncertain significance	not provided	2013-06-11	criteria provided, single submitter	clinical testing	p.Asn851Ser (AAT>AGT): c.2552 A>G in exon 14 of the SCN1A gene (NM_001165963.1) The Asn851Ser missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is conservative as both Asparagine and Serine are uncharged, polar amino acid residues. Asn851Ser alters a poorly conserved position between the third and fourth segments of the second transmembrane domain in the protein. However, another missense variant in this region of the protein (Glu853Lys) has been published as a de novo mutation in an individual with myoclonic epilepsy in infancy (Mancardi et al., 2006). In addition, while two in-silico algorithms predict Asn851Ser is non-pathogenic, another model predicts it may be damaging to the structure/function of the protein. Therefore, based on the currently available information, it is unclear whether Asn851Ser is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Lifecell International Pvt. Ltd	RCV001527713	SCV001738768	uncertain significance	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	A heterozygous missense variant (c.2552A>G) in exon 17 of the SCN1A gene that results in the amino acid substitution from Asparagine to Serine at codon 851 (p.Asn851Ser) was identified. The observed variant is reported in both the 1000 Genomes and gnomAD databases with minor allele frequency of 0.0200% and 0.0016% respectively. The reference base is conserved in mammals and in-silico predictions by SIFT is damaging. The Missense Variants Z-Score for this variant is 5.61. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). Based on the above evidence this variant has been classified as variant of uncertain significance according to the ACMG guidelines.
Invitae	RCV001852494	SCV002126087	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2021-10-27	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN1A protein function. ClinVar contains an entry for this variant (Variation ID: 206783). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. This variant is present in population databases (rs561912072, gnomAD 0.003%). This sequence change replaces asparagine, a(n) neutral and polar amino acid, with serine, a(n) neutral and polar amino acid, at codon 851 of the SCN1A protein (p.Asn851Ser).
CeGaT Center for Human Genetics Tuebingen	RCV000188891	SCV004703770	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SCN1A: PM2, PP2