Submissions for variant NM_001165963.4(SCN1A):c.4934G>A (p.Arg1645Gln)

dbSNP: rs121917976

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188986	SCV000242617	pathogenic	not provided	2020-07-06	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 19585586, 17347258, 16713920, 19359143, 19589774, 27864847, 31134136, 31031587)
Neurogenetics Laboratory - MEYER, AOU Meyer	RCV000059432	SCV000494514	pathogenic	Severe myoclonic epilepsy in infancy	2016-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002316217	SCV000851004	pathogenic	Inborn genetic diseases	2016-05-06	criteria provided, single submitter	clinical testing	The p.R1645Q pathogenic mutation (also known as c.4934G>A), located in coding exon 26 of the SCN1A gene, results from a G to A substitution at nucleotide position 4934. The arginine at codon 1645 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in the literature as de novo in two individuals with the SCN1A-related seizure disorder, Dravet syndrome (Harkin LA, Brain 2007; 130:843-52; Heron SE, J. Med. Genet. 2010; 47(2):137-41; Bolszak M, Epilepsy Res. 2009; 85(2-3):300-4). The position R1645 corresponds to a well-defined arginine (R3) in the voltage sensing motif known to play a significant role in gating function (DeCoursey TE. Physiol Rev. 2013;93(2):599-652). Based on the supporting evidence this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000763457	SCV000894234	pathogenic	Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198988	SCV001369983	pathogenic	Migraine, familial hemiplegic, 3	2018-11-28	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP3,PS1.
Invitae	RCV001208285	SCV001379664	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. ClinVar contains an entry for this variant (Variation ID: 68558). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17347258, 27864847). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs121917976, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1645 of the SCN1A protein (p.Arg1645Gln).
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000059432	SCV002072919	pathogenic	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	The missense variant p.R1645Q in SCN1A (NM_001165963.4) has ben previously reported in multiple patients with Dravet syndrome including one where it was confirmed to be de novo (Harkin LA et al; Parrini E et al). The variant has been submitted to ClinVar as Pathogenic.The missense variant c.4934G>A (p.R1645Q) in SCN1A (NM_001165963.4) is not observed in the large population cohorts of the gnomAD and 1000 Genomes datasets (Exome Aggregation Consortium et al., 2016; 1000 Genomes Consortium et al., 2015). The p.R1645Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 1645 of SCN1A is conserved in all mammalian species. The nucleotide c.4934 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot	RCV000059432	SCV000090956	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided