Submissions for variant NM_001165963.4(SCN1A):c.3152T>C (p.Leu1051Pro)

gnomAD frequency: 0.00001  dbSNP: rs776055539

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002316150	SCV000847756	likely benign	Inborn genetic diseases	2017-09-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862022	SCV002154494	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2024-03-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1051 of the SCN1A protein (p.Leu1051Pro). This variant is present in population databases (rs776055539, gnomAD 0.03%). 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: 588233). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV004788144	SCV005400970	uncertain significance	Developmental and epileptic encephalopathy 6B	2023-06-22	criteria provided, single submitter	clinical testing	The observed missense c.3152T>C(p.Leu1051Pro) variant in SCN1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.004% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Likely Benign/ Uncertain Significance. Computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster -Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid in SCN1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 1051 is changed to a Pro 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).