Submissions for variant NM_001165963.4(SCN1A):c.1738C>T (p.Arg580Ter)

dbSNP: rs794726736

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000180844	SCV000221809	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
GeneDx	RCV000254957	SCV000321937	pathogenic	not provided	2023-02-10	criteria provided, single submitter	clinical testing	Identified in siblings with Dravet syndrome and seizures with possible maternal mosaicism in published literature (Depienne et al., 2010); 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: 30945278, 25525159, 22151702, 24502503, 25754450, 30368457, 30619928, 31864146, 32090326, 34055682, 35074891, 34145886, 31440721, 25206388, 20110217, 26096185, 18930999, 20522430)
Invitae	RCV000544887	SCV000633815	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-01-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189892). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 18930999, 20110217, 20522430, 24502503, 25206388). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg580*) 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).
Lifecell International Pvt. Ltd	RCV000180844	SCV001739359	pathogenic	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	A heterozygous nonsense variation in exon 14 of the SCN1A gene (c.1738C>T) that results in a stop codon and premature truncation of the protein at codon 580 (p.Arg580Ter) was detected. The observed variant is not reported in 1000 genome database and gnomAD database. The reference base is conserved across the species and in-silico predictions by CADD and Mutation taster are damaging. The gene SCN1A has a low rate of benign loss of function variants as indicated by a high LoF variants Z-Score of 7.90. The p.Arg580Ter 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.Met1Ile and 385 others. There are 254 downstream pathogenic loss of function variants, with the furthest variant being 1346 residues downstream of the variant p.Arg580Ter. This variant has previously been reported for seizure-related syndromes by Kong et al., 2019. Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines.
Revvity Omics, Revvity	RCV000254957	SCV003827382	pathogenic	not provided	2022-08-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000180844	SCV004100765	pathogenic	Severe myoclonic epilepsy in infancy	2023-10-09	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP,PS2
PreventionGenetics, part of Exact Sciences	RCV003398874	SCV004110549	pathogenic	SCN1A-related condition	2023-02-11	criteria provided, single submitter	clinical testing	The SCN1A c.1738C>T variant is predicted to result in premature protein termination (p.Arg580*). This variant has been reported in multiple individuals with epilepsy/Dravet syndrome; in at least two patients it was reported to have occurred de novo, and in a third it was described as an inherited variant that was not detectable in the parents, suggesting parental germline mosaicism (Depienne et al. 2009. PubMed ID: 18930999; Takayama et al. 2014. PubMed ID: 24502503; Kong et al. 2018. PubMed ID: 30619928; Jiao et al. 2019. PubMed ID: 30945278). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Nonsense variants in SCN1A are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.