ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4135G>A (p.Val1379Met) (rs121917986)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Bioinformatics, Peking University RCV000059411 SCV000221778 pathogenic Severe myoclonic epilepsy in infancy 2014-12-20 criteria provided, single submitter research
GeneDx RCV000254970 SCV000322269 pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing The V1390M missense pathogenic variant in the SCN1A gene has been reported previously as a de novo pathogenic variant in association with Dravet syndrome and other SCN1A-related disorders (Kanai et al., 2004; Harkin et al., 2007; Sun et al., 2010; SCN1A Variant Database). 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 V1390M variant is a conservative amino acid substitution that occurs at a position where amino acids with similar properties to Valine are tolerated across species, and it is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the third homologous domain of the SCN1A protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same position (V1390L) and in nearby residues (F1385V, N1391S, H1393P, T1394I, D1395Y) 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.
Invitae RCV000804975 SCV000944916 pathogenic Early infantile epileptic encephalopathy 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1390 of the SCN1A protein (p.Val1390Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Dravet syndrome; in several of these cases, it was observed to be de novo (PMID: 12083760, 20431604, 23762420, 22780858, 29141279). This variant is also known as c.A3169G p.V1380M in the literature. ClinVar contains an entry for this variant (Variation ID: 68537). This variant identified in the SCN1A gene is located in the extracellular D3-P3 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot RCV000059411 SCV000090935 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided

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