Submissions for variant NM_001165963.4(SCN1A):c.4547C>T (p.Ser1516Leu) (rs139300715)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000209885	SCV000265507	uncertain significance	Severe myoclonic epilepsy in infancy	2021-09-01	criteria provided, single submitter	research
GeneDx	RCV000494091	SCV000582178	likely pathogenic	not provided	2015-09-25	criteria provided, single submitter	clinical testing	The S1516L 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. The S1516L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a highly conserved position predicted to be in the cytoplasmic loop between the third and fourth homologous domains. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, variants in nearby residues (A1510G, M1511R, L1514S, P1519T) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000702992	SCV000831870	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2018-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 1516 of the SCN1A protein (p.Ser1516Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs139300715, ExAC 0.02%). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 69406). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant identified in the SCN1A gene is located in the cytoplasmic interlinker D3-D4 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. 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.