ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.1178G>A (p.Arg393His) (rs121917927)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Bioinformatics, Peking University RCV000059378 SCV000221780 pathogenic Severe myoclonic epilepsy in infancy 2014-12-20 criteria provided, single submitter research
GeneDx RCV000188863 SCV000242493 pathogenic not provided 2017-06-14 criteria provided, single submitter clinical testing Arg393His has been reported previously as a de novo variant in patients with a clinical diagnosis of Dravet syndrome (Claes et al., 2003; Marini et al., 2007). Additionally, other missense substitutions at the same codon (Arg393Cys and Arg393Ser) have been reported as de novo variants in patients with epilepsy. Arg393His alters a highly conserved position in the pore loop between the S5 and S6 segments of the first transmembrane domain, and functional studies indicate that it significantly impairs channel function (Ohmori et al., 2006).
Athena Diagnostics Inc RCV000059378 SCV000255812 pathogenic Severe myoclonic epilepsy in infancy 2014-04-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000059378 SCV000697759 pathogenic Severe myoclonic epilepsy in infancy 2016-03-16 criteria provided, single submitter clinical testing Variant summary: The SCN1A c.1178G>A variant affects a conserved nucleotide, resulting in amino acid change from a large and basic Arg to a medium sized and polar His residue at codon 393. This variant is present in S5S6 linker region of the protein which forms the pore of the protein (Rilstone_2012). 4/4 in-silico tool predict a damaging outcome for this variant. Another pathogenic variant p.Arg393Cys has also been reported in this codon, suggesting that the p.Arg393 is important for protein function. Whole-cell patch-clamp studies of R393H show no measurable sodium channel activity, suggesting that this missense change results in a loss of function. This variant was found in 1/121376 control chromosomes including broad and large populations from ExAC at a frequency of 0.0000082, which is lower than the maximal expected frequency of a pathogenic SCN1A allele (0.0000179). The variant has been reported in at least 8 SMEI unrelated patients in literature across various ethnicities, and in one patient with SMEB and one with intractable childhood epilepsy. The variant has also been reported to originate do novo, strongly supporting for a pathogenic outcome. In addition, multiple clinical laboratories have classified this variant as pathogenic. Taken together, this variant was classified as Disease Variant/Pathogenic.
Invitae RCV000636386 SCV000757825 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2018-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 393 of the SCN1A protein (p.Arg393His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with severe myoclonic epilepsy of infancy (SMEI) (PMID: 12754708). It has also been reported in additional individuals affected with SMEI, severe myoclonic epilepsy of infancy, borderline phenotype (SMEB) and Dravet syndrome (PMID: 23195492, 22780858, 28544625). ClinVar contains an entry for this variant (Variation ID: 68506). Experimental studies have shown that this missense change results in a non-functional SCN1A protein channel (PMID: 17054685). A different missense substitution at this codon (p.Arg393Cys) has been determined to be pathogenic (PMID: 23934111, 21868258, 17054684). 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.
Mendelics RCV000059378 SCV001136058 pathogenic Severe myoclonic epilepsy in infancy 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188863 SCV001249702 pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198232 SCV001369102 likely pathogenic Familial hemiplegic migraine type 3 2019-06-22 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP2,PP3,PP5.
Institute of Human Genetics, University of Leipzig Medical Center RCV000059378 SCV001428687 pathogenic Severe myoclonic epilepsy in infancy 2019-11-19 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059378 SCV000090902 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000188863 SCV001808297 pathogenic not provided no assertion criteria provided clinical testing

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