Submissions for variant NM_001165963.4(SCN1A):c.4554dup (p.Pro1519fs)

dbSNP: rs794726825

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189062	SCV000242693	pathogenic	not provided	2014-12-15	criteria provided, single submitter	clinical testing	c.4554dupA: p.Pro1519ThrfsX18 (P1519TfsX18) in exon 24 of the SCN1A gene (NM_001165963.1). The normal sequence with the base that is duplicated in braces is: CGAAAAA{A}CCGC. The c.4554dupA mutation in the SCN1A gene was reported previously as c.4589insA using alternative nomenclature and was identified as a de novo mutation in an individual with Dravet syndrome (Marini et al., 2007). The duplication causes a frameshift starting with codon Proline 1519, changes this amino acid to a Threonine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Pro1519ThrfsX18. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, the presence of c.4554dupA is consistent with a diagnosis of an SCN1A-related disorder. The variant is found in EPILEPSYV2-1 panel(s).
Genetic Services Laboratory, University of Chicago	RCV000502228	SCV000596950	pathogenic	Seizure	2016-03-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517892	SCV003524815	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-08-17	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 206920). This sequence change creates a premature translational stop signal (p.Pro1519Thrfs*18) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SCN1A-related conditions (PMID: 17561957, 23195492, 31864146, 32090326). This variant is also known as c.4589insA (K1517ins1536X); c.4554-4555insA (P1519fsX1536). For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003992218	SCV004809797	uncertain significance	Severe myoclonic epilepsy in infancy	2024-04-04	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000502228	SCV001161946	pathogenic	Seizure		no assertion criteria provided	research
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV002281570	SCV002570039	pathogenic	Migraine, familial hemiplegic, 3	2002-09-08	no assertion criteria provided	research