Submissions for variant NM_001040142.2(SCN2A):c.4607G>A (p.Ser1536Asn)

dbSNP: rs1044510361

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520071	SCV000617765	uncertain significance	not provided	2015-11-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SCN2A gene. The S1536N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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. This substitution alters a position that is conserved in mammals and is predicted to be within transmembrane segment S1 in the fourth homologous domain of the SCN2A protein. However, the S1536N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051541	SCV001215699	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1536 of the SCN2A protein (p.Ser1536Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 449529). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN2A protein function. 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.
Ambry Genetics	RCV004023544	SCV004944219	uncertain significance	Inborn genetic diseases	2023-12-29	criteria provided, single submitter	clinical testing	The c.4607G>A (p.S1536N) alteration is located in exon 26 (coding exon 25) of the SCN2A gene. This alteration results from a G to A substitution at nucleotide position 4607, causing the serine (S) at amino acid position 1536 to be replaced by an asparagine (N). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, c.4608C>A (p.S1536R), has been detected in an individual with clinical features consistent with SCN2A-related neurodevelopmental disorder (Wolff, 2017). This amino acid position is poorly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004722860	SCV005339929	uncertain significance	SCN2A-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The SCN2A c.4607G>A variant is predicted to result in the amino acid substitution p.Ser1536Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. An alternate missense variant (p.Ser1536Arg) has been reported to occur de novo in an individual with encephalopathy with early-onset epilepsy (Wolff et al. 2017. PubMed ID: 28379373). At this time, the clinical significance of the c.4607G>A (p.Ser1536Asn) is uncertain due to the absence of conclusive functional and genetic evidence.