Submissions for variant NM_001165963.4(SCN1A):c.4933C>T (p.Arg1645Ter)

dbSNP: rs794726759

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000180873	SCV000221842	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV001090360	SCV001245864	pathogenic	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001580464	SCV001810214	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2021-07-22	criteria provided, single submitter	clinical testing
DASA	RCV001813764	SCV002061222	pathogenic	Migraine, familial hemiplegic, 3	2022-01-05	criteria provided, single submitter	clinical testing	The c.4933C>T;p.(Arg1645*) variant creates a premature translational stop signal in the SCN1A gene. It is expected to result in an absent or disrupted protein product -PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 189921; PMID: 26096185; 19809937) - PS4_moderate. This variant is not present in population databases (rs794726759, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 19809937) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.
Invitae	RCV001850418	SCV002220516	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-08-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SCN1A protein in which other variant(s) (p.Arg1924Leufs*8) have been determined to be pathogenic (PMID: 27465585). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 189921). This variant is also known as R1635X. This premature translational stop signal has been observed in individual(s) with Dravet syndrome and/or severe myoclonic epilepsy in infancy (PMID: 14738421, 19809937, 29141279). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1645*) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 365 amino acid(s) of the SCN1A protein.
GeneDx	RCV001090360	SCV004014420	pathogenic	not provided	2023-01-12	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 391 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29453127, 29141279, 19809937, 32090326, 29573403, 32092540, 14738421, 31302675, 26096185)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000180873	SCV001364269	pathogenic	Severe myoclonic epilepsy in infancy	2020-02-19	no assertion criteria provided	clinical testing