Submissions for variant NM_001165963.4(SCN1A):c.5504_5512del (p.Leu1835_Pro1837del)

dbSNP: rs797044983

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190447	SCV000245326	pathogenic	not provided	2013-08-08	criteria provided, single submitter	clinical testing	c.5504_5512delTTGAACCGC: p.Leu1835_Pro1837del (L1835_P1837del) in exon 26 of the SCN1A gene (NM_006920.4). The normal sequence with the bases that are deleted in braces is: GCGC{TTGAACCGC}CTCT. The c.5504_5512delTTGAACCGC variant in the SCN1A gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It results in an in-frame deletion of three conserved amino acids in the C-terminal region of the protein, beginning at codon Leucine 1835 and ending at codon Proline 1837. A missense mutation that alters one of the amino acids deleted (Leu1835Phe), has been previously published in association with Dravet syndrome (Depienne et al., 2009). Additionally, multiple other missense mutations have been reported at nearby codons in an external mutation database, confirming the functional importance of this region of the protein. Therefore, based on the currently available information, c.5504_5512delTTGAACCGC is a strong candidate for a disease-causing mutation. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089966	SCV005815637	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-08-01	criteria provided, single submitter	clinical testing	This variant, c.5504_5512del, results in the deletion of 3 amino acid(s) of the SCN1A protein (p.Leu1835_Pro1837del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of SCN1A-related conditions (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 208410). This variant disrupts a region of the SCN1A protein in which other variant(s) (p.Leu1835Phe) have been determined to be pathogenic (PMID: 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. For these reasons, this variant has been classified as Pathogenic.