Submissions for variant NM_001165963.4(SCN1A):c.3454T>A (p.Ser1152Thr)

gnomAD frequency: 0.00001  dbSNP: rs763254451

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686810	SCV000814345	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1152 of the SCN1A protein (p.Ser1152Thr). This variant is present in population databases (rs763254451, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 566881). 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) has been performed at Invitae 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 SCN1A 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.
GeneDx	RCV001766467	SCV001991806	uncertain significance	not provided	2019-03-27	criteria provided, single submitter	clinical testing	The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Predicted to be in the cytoplasmic loop between the second and third homologous domains
Lifecell International Pvt. Ltd	RCV003126903	SCV003804168	uncertain significance	Generalized epilepsy with febrile seizures plus, type 2		criteria provided, single submitter	clinical testing	The missense variant NM_001165963.4(SCN1A):c.3454T>A (p.Ser1152Thr) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser1152Thr variant is novel from South Asian background in gnomAD. The p.Ser1152Thr variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between serine and threonine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene SCN1A has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 5.22. The gene SCN1A contains 418 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.Ser1152Thr missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 1152 of SCN1A is conserved in all mammalian species. The nucleotide c.3454 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. This variant was found in ClinVar (Variant 566881) with a classification of Uncertain Significance and a review status of (1 stars) criteria provided, single submitter. For these reasons, this variant has been classified as Uncertain Significance.