Submissions for variant NM_001165963.4(SCN1A):c.4884T>A (p.Tyr1628Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV002510640	SCV002820136	uncertain significance	Generalized epilepsy with febrile seizures plus, type 2		criteria provided, single submitter	clinical testing	This variant has not been reported in affected individuals. The nucleotide change in SCN1A is predicted as conserved by PhyloP across 100 vertebrates. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is a loss of function variant but since it is present in the last exon, functional studies will be required to prove protein truncation. Hence this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002569439	SCV003524785	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-07-22	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). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 12821740; Invitae). 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.Tyr1628*) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 382 amino acid(s) of the SCN1A protein.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003493962	SCV004244365	pathogenic	Severe myoclonic epilepsy in infancy	2024-01-30	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP