ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4514C>T (p.Ser1505Leu) (rs139300715)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000209885 SCV000265507 likely benign Severe myoclonic epilepsy in infancy 2017-02-09 criteria provided, single submitter research
Invitae RCV000702992 SCV000831870 uncertain significance Early infantile epileptic encephalopathy 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.

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