Submissions for variant NM_001165963.4(SCN1A):c.2837G>A (p.Arg946His)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000059395	SCV000255821	pathogenic	Severe myoclonic epilepsy in infancy	2015-06-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000378734	SCV000329631	pathogenic	not provided	2022-04-13	criteria provided, single submitter	clinical testing	Published functional studies suggest that R946H results in complete loss of function of the Nav1.1 protein (Liao et al., 2010; Volkers et al., 2011); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This substitution is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the second homologous domain; This variant is associated with the following publications: (PMID: 15508916, 18930999, 15277629, 16713920, 17347258, 16713913, 21371021, 17166794, 20550552, 14738421, 23195492, 21864321, 27781031, 19589774, 28492532, 15944908, 31780880, 32090326, 33851778)
Invitae	RCV000543457	SCV000633835	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 946 of the SCN1A protein (p.Arg946His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SCN1A-related epilepsy (PMID: 14738421, 19589774, 20550552, 21371021, 21864321, 23195492, 27781031). In at least one individual the variant was observed to be de novo. This variant is also known as R936H. ClinVar contains an entry for this variant (Variation ID: 68523). 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. Experimental studies have shown that this missense change affects SCN1A function (PMID: 20550552, 21864321). This variant disrupts the p.Arg946 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14738421, 21864321). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000059395	SCV000697762	pathogenic	Severe myoclonic epilepsy in infancy	2016-09-16	criteria provided, single submitter	clinical testing	Variant summary: The SCN1A c.2837G>A (p.Arg946His) variant involves the alteration of a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Histidine (H) located in the in the pore loop region of the SCN1A gene. 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121408 control chromosomes while it was reported in several Dravet Syndrome patients, some of whom the variant arose de novo, strongly indicating causality. Moreover, independent functional studies reported the variant to result in absent measurable sodium currents, further supporting pathogenicity. In addition, mutations affecting the same codon have been described as pathogenic (c.2837G>A, p.R946P; c.2836C>A, p.R946S; c.2836C>T, p.R946C; HGMD, ClinVar) underscoring the functional/clinical importance of the R946 residue and indicating the variant to be located in a mutation hotspot. Furthermore, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001004709	SCV001164174	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2018-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000378734	SCV001248478	pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001264404	SCV001442519	pathogenic	Seizure	2020-11-10	criteria provided, single submitter	clinical testing	Missense variant predicted pathogenic by bioinformatic scores. Absent from gnomAD but recurrent in the literature.
Ambry Genetics	RCV002433566	SCV002748458	likely pathogenic	Inborn genetic diseases	2017-12-14	criteria provided, single submitter	clinical testing	The p.R946H variant (also known as c.2837G>A), located in coding exon 15 of the SCN1A gene, results from a G to A substitution at nucleotide position 2837. The arginine at codon 946 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in multiple individuals with seizure disorders, including Dravet syndrome, severe myoclonic epilepsy in infancy, and generalized epilepsy with febrile seizures plus (GEFS+), occurring both de novo as well as inherited (Harkin LA et al. Brain, 2007 Mar;130:843-52; Depienne C et al. J. Med. Genet., 2009 Mar;46:183-91; Liao WP et al. Epilepsia, 2010 Sep;51:1669-78; Zuberi SM et al. Neurology, 2011 Feb;76:594-600; Verbeek NE et al. Epilepsia, 2011 Apr;52:e23-5; Volkers L et al. Eur. J. Neurosci., 2011 Oct;34:1268-75; Wang JW et al. Epilepsy Res., 2012 Dec;102:195-200; Møller RS et al. Mol Syndromol, 2016 Sep;7:210-219). In addition, when transfected into tsA201 cells, this variant demonstrated no measurable sodium currents when expressed heterologously with the recombinant human accessory sodium channel subunits β1 and β2 (Liao WP et al. Epilepsia, 2010 Sep;51:1669-78; Volkers L et al. Eur. J. Neurosci., 2011 Oct;34:1268-75). This amino acid position is highly 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.
UniProtKB/Swiss-Prot	RCV000059395	SCV000090919	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000378734	SCV001926274	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000378734	SCV001955087	pathogenic	not provided		no assertion criteria provided	clinical testing