ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4219C>T (p.Arg1407Ter) (rs398123593)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079581 SCV000111463 pathogenic not provided 2013-05-09 criteria provided, single submitter clinical testing
Invitae RCV000636415 SCV000757854 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-09-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1407*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with severe myoclonic epilepsy in infancy (PMID: 11940708). It has also been found in an individual with atypical Dravet syndrome (PMID: 24502503). This variant is also known as 4186C>T and Arg1396X in the literature. ClinVar contains an entry for this variant (Variation ID: 93649). Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000720923 SCV000851807 pathogenic History of neurodevelopmental disorder 2016-06-08 criteria provided, single submitter clinical testing The p.R1407* pathogenic mutation (also known as c.4219C>T and p.R1396*), located in coding exon 21 of the SCN1A gene, results from a C to T substitution at nucleotide position 4219. This changes the amino acid from an arginine to a stop codon within coding exon 21. This mutation was reported as a de novo mutation in a male proband with severe myoclonic epilepsy in infancy, whose convulsions were ofteninduced by fever or hot bath and were prone to occur in status epilepticus or in cluster (Sugawara T, et al. Neurology 2002; 58(7):1122-4). In addition, this mutation has been introduced into mice in two separate studies with similar outcomes, which include epileptic recurrent seizures, neuronal excitability, and cardiac electrophysiological abnormalities (Ogiwara I, et al. J. Neurosci. 2007;27(22):5903-14; Auerbach DS, et al. PLoS ONE 2013;8(10):e77843). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
GeneDx RCV000079581 SCV000890253 pathogenic not provided 2020-11-27 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17537961, 24155976, 25525159, 20831750, 24152123, 29329111, 29915537, 29141279, 25855492, 26749013, 25042160, 24502503, 15880351, 11940708, 16713920, 16458823, 30368457, 30868114, 31864146, 31765958)
LifeCell International Pvt. Ltd RCV001509554 SCV001712085 pathogenic Severe myoclonic epilepsy in infancy criteria provided, single submitter clinical testing A heterozygous nonsense variation in exon 24 of the SCN1A gene (c.4219C>T) that results in a stop codon and premature truncation of the protein at codon 1407 (p.Arg1407Ter) was detected. The observed variant is not reported in 1000 genome database and gnomAD database. The reference base is conserved across the species and in-silico predictions by CADD and Mutation taster are damaging. This variant is predicted to cause loss of normal protein function through protein truncation. The gene SCN1A has a low rate of benign loss of function variants as indicated by a high LoF variants Z-Score of 7.90. The p.R1407Ter variant is a loss of function variant in the gene SCN1A, 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 449 others. There are 112 downstream pathogenic loss of function variants, with the furthest variant being 519 residues downstream of the variant p.R1407Ter. This variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 93649 as of 2021-02-04). Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines.

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