Submissions for variant NM_001165963.4(SCN1A):c.3985C>T (p.Arg1329Ter)

dbSNP: rs796053004

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188938	SCV000242569	pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Reported previously as a maternally inherited variant in siblings with Dravet syndrome; their mother was mosaic for the variant with a history of migraines (Selmer et al., 2009); 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, 22719002, 24836964, 21248271, 21269283, 18413471, 19400878, 22409937, 16430863, 15880351, 15508915, 25754450, 22151702, 31164858, 31864146, 32090326, 35074891, 35813073, 18930999, 19673951)
Athena Diagnostics Inc	RCV000201135	SCV000255827	pathogenic	Severe myoclonic epilepsy in infancy	2014-10-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622874	SCV000741558	pathogenic	Inborn genetic diseases	2022-06-08	criteria provided, single submitter	clinical testing	The c.3985C>T (p.R1329*) alteration, located in coding exon 20 of the SCN1A gene, consists of a C to T substitution at nucleotide position 3985. This changes the amino acid from a Arginine (R) to a stop codon at amino acid position 1329. 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.3985C>T (p.R1329*) 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 unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with Dravet syndrome (Demos, 2019; Depienne, 2009; Gertler, 2020; Selmer, 2009; Zuberi, 2011). Based on the available evidence, this alteration is classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000201135	SCV001429123	pathogenic	Severe myoclonic epilepsy in infancy	2017-11-17	criteria provided, single submitter	clinical testing
Invitae	RCV001385509	SCV001585388	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-08-07	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: 206816). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 18930999, 25754450). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1329*) 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).
Revvity Omics, Revvity	RCV000188938	SCV002020010	pathogenic	not provided	2019-03-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470805	SCV002769487	pathogenic	Developmental and epileptic encephalopathy, 6	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN1A-related epilepsy (PMID: 28488083). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variant comparable to the one identified in this case have very strong previous evidence for pathogenicity. NMD-predicted variants are well-reported as pathogenic in ClinVar and the literature (PMID: 18930999). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. It has also been reported in the literature de novo in an individual with Dravet syndrome (PMID: 18930999). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001194614	SCV001364268	pathogenic	Generalized epilepsy with febrile seizures plus, type 2	2020-02-19	no assertion criteria provided	clinical testing