Submissions for variant NM_001165963.4(SCN1A):c.1702C>T (p.Arg568Ter)

dbSNP: rs886039430

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254726	SCV000321925	pathogenic	not provided	2016-10-21	criteria provided, single submitter	clinical testing	The R568X nonsense variant in the SCN1A gene has been reported multiple times previously in association withSCN1A-related disorders (Ohmori et al., 2002; SCN1A Variant Database). Functional studies suggest that the R568Xvariant results in a nonfunctional Nav1.1 protein (Ohmori et al., 2008). This pathogenic variant is predicted to causeloss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768077	SCV000898949	pathogenic	Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2	2017-12-04	criteria provided, single submitter	clinical testing	SCN1A: NM_01165963.1 exon11 p.Arg568* (c.1702C>T): This variant has been reported in the literature in at least 1 individual with Dravet syndrome, as a de novo variant (Ohmori 2002, PMID:12083760, Ohmori 2008 PMID:18755274, Okumura 2012, PMID:22092154). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID: 265254). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies for this variant are unclear (Ohmori 2008, PMID18755274). However, this variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic based on presence of this variant as de novo in an affected individual, absence from controls and predicted impact to the protein.
CeGaT Center for Human Genetics Tuebingen	RCV000254726	SCV001249699	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198880	SCV001369875	pathogenic	Migraine, familial hemiplegic, 3	2018-09-28	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4,PM2,PM4.
Invitae	RCV001382872	SCV001581826	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg568*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 12083760, 29852413). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265254). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000254726	SCV002503320	pathogenic	not provided	2020-05-11	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224247	SCV003920418	pathogenic	Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2; Developmental and epileptic encephalopathy 6B	2021-11-11	criteria provided, single submitter	clinical testing	SCN1A: NM_01165963 exon11 p.Arg568X (c.1702C>T): This variant has been reported in the literature in at least 1 individual with Dravet syndrome, as a de novo variant (Ohmori 2002, PMID:12083760, Ohmori 2008 PMID:18755274, Okumura 2012, PMID:22092154). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID: 265254). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies for this variant are unclear (Ohmori 2008, PMID18755274). However, this variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic based on presence of this variant as de novo in an affected individual, absence from controls and predicted impact to the protein.
Ambry Genetics	RCV003362739	SCV004072574	pathogenic	Inborn genetic diseases	2023-06-26	criteria provided, single submitter	clinical testing	The c.1702C>T (p.R568*) alteration, located in exon 11 (coding exon 11) of the SCN1A gene, consists of a C to T substitution at nucleotide position 1702. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 568. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although loss of function alterations in SCN1A have been associated with Dravet syndrome, haploinsufficiency for SCN1A has not been established as a mechanism of disease for SCN1A-related developmental and epileptic encephalopathy, SCN1A-related hemiplegic migraine, and SCN1A-related GEFS+. Based on the available evidence, the SCN1A c.1702C>T (p.R568*) alteration is classified as pathogenic for Dravet syndrome; however, its clinical significance for SCN1A-related developmental and epileptic encephalopathy, SCN1A-related hemiplegic migraine, and SCN1A-related GEFS+ is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in the heterozygous state in multiple individuals with Dravet syndrome and was reported as de novo in at least one individual (Brunklaus, 2022; Damiano, 2020; Gertler, 2020; Gowda, 2023; Kothur, 2018; Villeneuve, 2014; Okumura 2012; Ohmori, 2008; Ohmori, 2002). Based on the available evidence, this alteration is classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001194613	SCV001364267	pathogenic	Severe myoclonic epilepsy in infancy	2020-02-19	no assertion criteria provided	clinical testing