Submissions for variant NM_001165963.4(SCN1A):c.4168G>A (p.Val1390Met) (rs121917986)

Total submissions: 6

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 with suppression bursts	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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000254970	SCV001740812	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000254970	SCV001931131	pathogenic	not provided		no assertion criteria provided	clinical testing