Submissions for variant NM_001165963.4(SCN1A):c.2593C>T (p.Arg865Ter)

dbSNP: rs794726697

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000180798	SCV000221753	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
GeneDx	RCV000423112	SCV000515825	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	Reported in patients with intractable epilepsy and Dravet syndrome in the published literature (PMID: 21868258, 23195492); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 29852413, 32090326, 33278787, 21868258, 35074891, 33057194, 35982159, 31864146, 31440721, 36265913, 29778030, 37644014, 29314583, 23195492, 12083760)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530080	SCV000633831	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg865*) 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, severe myoclonic epilepsy in infancy, and intractable epilepsy (PMID: 12083760, 18076640, 18930999, 21868258, 23195492). This variant is also known as C2560T (R854X). ClinVar contains an entry for this variant (Variation ID: 189844). For these reasons, this variant has been classified as Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001786337	SCV002028390	pathogenic	Seizure	2021-12-01	criteria provided, single submitter	clinical testing	de novo truncating variant.
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV000180798	SCV002583256	pathogenic	Severe myoclonic epilepsy in infancy	2022-10-05	criteria provided, single submitter	research
Lifecell International Pvt. Ltd	RCV000180798	SCV003804183	pathogenic	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	"A heterozygous nonsense variation in exon 18 of the SCN1A gene (c.2593C>T) that results in a stop codon and premature truncation of the protein at codon 865 (p.Arg865Ter) was detected. The observed variant is not reported in gnomAD database and 1000 genome database. The reference base is conserved across the species and in-silico predictions by CADD and Mutation taster are damaging. This variant is a stop gained variant which occurs in an exon of SCN1A upstream of where nonsense mediated decay is predicted to occur. There are 239 downstream pathogenic loss of function variants, with the furthest variant being 1061 residues downstream of this variant. This indicates that the region is critical to protein function. The gene SCN1A has a low rate of benign loss of function variants as indicated by a low upper bound of the observed/expected confidence interval 0.07. The p.Arg865Ter variant is a loss of function variant in the gene SCN1A, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_001159435.1:p.M1I and 452 others. The variant p.Arg865Ter has been previously classified as Pathogenic in ClinVar (Variation ID 189844 as of 2021-04-01) with respect to Severe myoclonic epilepsy in infancy and 2 other conditions with a status of (2 stars) criteria provided, multiple submitters, no conflicts. Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines."
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000180798	SCV001364266	pathogenic	Severe myoclonic epilepsy in infancy	2020-02-19	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004725018	SCV005340837	pathogenic	SCN1A-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The SCN1A c.2593C>T variant is predicted to result in premature protein termination (p.Arg865*). In the literature, this variant is also referred to as C2560T or R837X using alternative transcripts. This variant has been reported in individuals with Dravet syndrome and other epilepsy phenotypes (see, for example, Ohmori et al. 2002. PubMed ID: 12083760; Lim et al. 2011. PubMed ID: 21868258; E-Table A, Wang et al. 2012. PubMed ID: 23195492; Zhou et al. 2018. PubMed ID: 29314583). It occurred de novo in multiple individuals (Ohmori et al. 2002. PubMed ID: 12083760; Zhou et al. 2018. PubMed ID: 29314583; Wang et al. 2021. PubMed ID: 33278787) and in one family, an unaffected parent was found to be mosaic for this variant (Xu et al. 2015. PubMed ID: 26096185). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in SCN1A are expected to be pathogenic. This variant is interpreted as pathogenic.