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

dbSNP: rs121917986

Total submissions: 8

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	2021-11-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the third homologous domain; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20431604, 26096185, 31864146, 12083760, 17347258, 15277629, 22780858, 31879226, 29141279, 33108073, 23762420, 31031587, 18804930)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804975	SCV000944916	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1390 of the SCN1A protein (p.Val1390Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 12083760, 20431604, 22780858, 23762420, 29141279, 30182498). In at least one individual the variant was observed to be de novo. This variant is also known as c.A3169G p.V1380M. ClinVar contains an entry for this variant (Variation ID: 68537). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002326783	SCV002630430	likely pathogenic	Inborn genetic diseases	2018-06-20	criteria provided, single submitter	clinical testing	The p.V1390M variant (also known as c.4168G>A), located in coding exon 21 of the SCN1A gene, results from a G to A substitution at nucleotide position 4168. The valine at codon 1390 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in several individuals with clinical diagnoses of Dravet syndrome (Aljaafari D et al. Epilepsia, 2017 03;58:e44-e48; Rilstone JJ et al. Epilepsia, 2012 Aug;53:1421-8; Cho MJ et al. J Clin Neurol, 2018 Jan;14:22-28) and as a de novo occurrence in an individual with borderline severe myoclonic epilepsy of infancy (SMEI) (Sun H et al. Epilepsia, 2008 Jun;49:1104-7). In addition, a different alteration located at the same position, p.V1390L (c.4168G>T), has been detected in an individual with Dravet syndrome and co-segregated with disease in a family with a variable epilepsy phenotype (Tian X et al. Dev Med Child Neurol, 2018 06;60:566-573; Mhanni AA et al. Seizure, 2011 Nov;20:711-2). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000059411	SCV003921062	pathogenic	Severe myoclonic epilepsy in infancy	2023-02-08	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS4_MOD, PM5, PM1_SUP, PM2_SUP,PP2, PP3
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