Submissions for variant NM_001165963.4(SCN1A):c.5010_5013del (p.Phe1671fs)

dbSNP: rs794726754

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000180866	SCV000221831	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
GeneDx	RCV000189065	SCV000242696	pathogenic	not provided	2014-08-19	criteria provided, single submitter	clinical testing	c.5010_5013delGTTT: p.Phe1671ThrfsX8 (F1671TfsX8) in exon 26 of the SCN1A gene (NM_001165963.1). The normal sequence with the bases that are deleted in braces is: CGTT{GTTT}AACA. The c.5010_5013delGTTT mutation in the SCN1A gene has been reported previously as a de novo mutation in association with SCN1A-related disorders (Claes et al., 2001; Depienne et al., 2009). The deletion causes a frameshift starting with codon Phenylalanine 1671, changes this amino acid to a Threonine residue and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Phe1671ThrfsX8. This mutation is predicted to cause loss of normal protein function through protein truncation as the last 339 amino acids of the SCN1A protein are replaced with 7 incorrect amino acids. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798624	SCV000938249	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-08-08	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with Dravet syndrome and early infantile epileptic encephalopathy (PMID: 11359211, 26993267). In at least one individual the variant was observed to be de novo. 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.Lys1846Serfs*11, p.Arg1886*) have been determined to be pathogenic (PMID: 11359211, 14504318, 17054684, 18930999, 21719429). 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: 189914). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe1671Thrfs*8) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 339 amino acid(s) of the SCN1A protein.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000180866	SCV001950118	pathogenic	Severe myoclonic epilepsy in infancy	2021-11-19	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP
Genetic Services Laboratory, University of Chicago	RCV000189065	SCV002064459	pathogenic	not provided	2017-08-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000189065	SCV004147168	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	SCN1A: PS2:Very Strong, PM2
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003954	SCV001161944	pathogenic	Epileptic encephalopathy		no assertion criteria provided	research