ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.2836C>T (p.Arg946Cys) (rs121918775)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000118240 SCV000152602 pathogenic Generalized epilepsy with febrile seizures plus, type 2 2013-11-26 criteria provided, single submitter clinical testing
Center for Bioinformatics, Peking University RCV000059481 SCV000221901 pathogenic Severe myoclonic epilepsy in infancy 2014-12-20 criteria provided, single submitter research
GeneDx RCV000189085 SCV000242716 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing The R946C missense variants in the SCN1A gene has been reported multiple times in association with SCN1A-related disorders (Fukuma et al., 2004; Volkers et al., 2011). Functional studies have suggested that R946C affects the sodium channels and lead to a complete loss of ion channel function (Volkers et al., 2011). The R946C variant is a non-conservative amino acid substitution, and alters a highly conserved position in the pore loop between the S5 and S6 transmembrane segments of the second homologous domain of the SCN1A protein (Escayg et al., 2010). Different missense variants in the same residue (R946S, R946H, R946P) as well as multiple missense variants in nearby residues have been reported in association with SCN1A-related disordersin an external variant database, supporting the functional importance of this region of the protein. Therefore, the presence of R946C is consistent with a diagnosis of a SCN1A-related disorder.
Athena Diagnostics Inc RCV000059481 SCV000255820 pathogenic Severe myoclonic epilepsy in infancy 2015-04-15 criteria provided, single submitter clinical testing
Invitae RCV000636276 SCV000757715 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 946 of the SCN1A protein (p.Arg946Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with Dravet syndrome  (PMID:14738421, 21864321, 23195492). This variant is also known as R936C in the literature. ClinVar contains an entry for this variant (Variation ID: 68604). This variant identified in the SCN1A gene is located in the extracellular D2-P2 region of the resulting protein (PMID: 25348405, 18804930). Experimental studies have demonstrated that this missense change did not produce measurable sodium currents (PMID: 21864321). A different missense substitution at this codon (p.Arg936His) has been determined to be pathogenic (PMID: 21864321, 27781031, 23195492, 21371021). This suggests that the arginine residue is critical for SCN1A protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000189085 SCV001248479 pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059481 SCV000091006 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000189085 SCV001739774 pathogenic not provided no assertion criteria provided clinical testing

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