Submissions for variant NM_001165963.4(SCN1A):c.4906C>T (p.Arg1636Ter)

dbSNP: rs199727342

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000180823	SCV000221787	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
GeneDx	RCV000188982	SCV000242613	pathogenic	not provided	2022-02-25	criteria provided, single submitter	clinical testing	Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#: 189870; ClinVar); Not observed in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 374 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 26467025, 21248271, 28202706, 21868258, 30034362, 32090326, 33278787, 31031587, 29655203, 34163418)
Athena Diagnostics Inc	RCV000180823	SCV000255831	pathogenic	Severe myoclonic epilepsy in infancy	2012-11-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000188982	SCV000336787	pathogenic	not provided	2015-11-06	criteria provided, single submitter	clinical testing
Invitae	RCV000804066	SCV000943960	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-12-02	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.Arg1886*) have been determined to be pathogenic (PMID: 17054684, 18930999; Invitae). 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: 189870). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 21248271, 21868258, 28202706). 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.Arg1636*) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 374 amino acid(s) of the SCN1A protein.
CeGaT Center for Human Genetics Tuebingen	RCV000188982	SCV001245866	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV003128152	SCV003804179	pathogenic	Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2; Developmental and epileptic encephalopathy 6B		criteria provided, single submitter	clinical testing	The stop gained NM_001165963.4 (SCN1A):c.4906C>T (p.Arg1636Ter) has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 189870 as of 2021-11-04). The p.Arg1636Ter variant is novel (not in any individuals) in gnomAD. The p.Arg1636Ter variant is novel (not in any individuals) in 1kG. This variant is predicted to cause loss of normal protein function through protein truncation. This variant has been previously classified as pathogenic, indicating that the region is critical to protein function. There are 66 downstream pathogenic loss of function variants, with the furthest variant being 297 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.Arg1636Ter 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 513 others. The c.4906C>T variant in SCN1A is predicted conserved by GERP++ and PhyloP and damaging by CADD. This variant has previously been reported for focal epilepsy by Meng-Han Tsai et al., 2018. For these reasons, this variant has been classified as Pathogenic.