Submissions for variant NM_001165963.4(SCN1A):c.5273_5277del (p.Asn1758fs)

dbSNP: rs796053085

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189066	SCV000242697	pathogenic	not provided	2015-01-05	criteria provided, single submitter	clinical testing	c.5273_5277delACCCA: p.Asn1758IlefsX35 (N1758IfsX35) in exon 26 of the SCN1A gene (NM_001165963.1). The normal sequence with the bases that are deleted in braces is: GGGA{ACCCA}TCTG. The c.5273_5277delACCCA mutation in the SCN1A gene causes a frameshift starting with codon Asparagine 1758, changes this amino acid to an Isoleucine residue and creates a premature Stop codon at position 35 of the new reading frame, denoted p.Asn1758IlefsX35. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this mutation has not been previously reported to our knowledge, other truncating mutations in the SCN1A gene have been reported in association with SCN1A-related disorders in an external mutation database. Therefore, the presence of c.5273_5277delACCCA is consistent with a diagnosis of an SCN1A-related disorder. The variant is found in INFANTV2-EPIV2-1 panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857650	SCV002122036	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2021-03-14	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with epilepsy and/or neurodevelopmental disorder (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 206923). This variant disrupts the C-terminus of the SCN1A protein. Other variant(s) that disrupt this region (p.Ala1919Leufs*13) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Asn1758Ilefs*35) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 252 amino acid(s) of the SCN1A protein.