ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5536_5539del (p.Lys1846fs) (rs794726726)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Bioinformatics, Peking University RCV000180834 SCV000221798 pathogenic Severe myoclonic epilepsy in infancy 2014-12-20 criteria provided, single submitter research
GeneDx RCV000189067 SCV000242698 pathogenic not provided 2018-08-28 criteria provided, single submitter clinical testing The c.5536_5539delAAAC variant in the SCN1A gene has been reported previously as de novo in multiple unrelated individuals in association with a SCN1A-related disorder (Xu et al., 2015; Mancardi et al., 2006; Claes et al., 2001; Wallace et al., 2003; Catarino et al., 2011). The c.5536_5539delAAAC variant causes a frameshift starting with codon Lysine 1846, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Lys1846SerfsX11. This variant is predicted to cause loss of normal protein function through protein truncation and is lost within the cytoplasmic topological domain and IQ domain at the C-terminal. The c.5536_5539delAAAC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.5536_5539delAAAC as a pathogenic variant
Invitae RCV000555321 SCV000633873 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2018-12-10 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotide from exon 26 of the SCN1A mRNA (c.5536_5539delAAAC), causing a frameshift at codon 1846. This creates a premature translational stop signal in the last exon of the SCN1A mRNA (p.Lys1846Serfs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 164 amino acids of the SCN1A protein. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo in individuals affected with Dravet syndrome (also known as severe myoclonic epilepsy of infancy) (PMID: 11359211, 14504318, 21719429). ClinVar contains an entry for this variant (Variation ID: 189881). For these reasons, this variant has been classified as Pathogenic.
LifeCell International Pvt. Ltd RCV000180834 SCV001754811 pathogenic Severe myoclonic epilepsy in infancy criteria provided, single submitter clinical testing A heterozygous one-base pair deletion in exon 29 of the SCN1A gene (c.5536_5539delAAAC) that results in a frameshift and premature truncation of the protein 11 amino acids downstream to codon 1846(p.K1846SfsTer11) was detected. This frameshift variant is not reported in both the 1000 genomes and gnomAD databases. This variant is predicted to be damaging by Mutation taster and the region is conserved across species. There are 14 downstream pathogenic loss of function variants, with the furthest variant being 80 residues downstream of this variant. This indicates that the region is critical to protein function. This gene has a low rate of benign loss of function variants as indicated by a low upper bound of the observed/expected confidence interval 0.07. The observed variant is a loss of function variant in this gene, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_001159435.1:p.M1I and 448 others. The observed variant has been previously classified as Pathogenic in ClinVar (Variation ID 189881 as of 2021-03-04) with respect to severe myoclonic epilepsy in infancy and 2 other conditions with a status of (2 stars) criteria provided, multiple submitters, no conflicts. Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines.

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