Submissions for variant NM_001040142.2(SCN2A):c.2860G>A (p.Ala954Thr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003060778	SCV003455430	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 954 of the SCN2A protein (p.Ala954Thr). This variant is present in population databases (rs749485469, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 33004838). ClinVar contains an entry for this variant (Variation ID: 2147205). 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 expected to disrupt SCN2A protein function with a positive predictive value of 95%. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV003340613	SCV004047547	uncertain significance	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing	The missense variant in c.2860G>A in SCN2A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala954Thr variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.001061% in gnomAD database. This variant has not been reported to the ClinVar database. The amino acid change p.Ala954Thr in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 954 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).
GeneDx	RCV004725504	SCV005333459	uncertain significance	not provided	2023-10-09	criteria provided, single submitter	clinical testing	Identified in an individual with a neurodevelopmental disorder, but segregation and detailed clinical information was not provided (Wang et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the second homologous domain; This variant is associated with the following publications: (PMID: 33004838)