ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.1738C>T (p.Arg580Ter) (rs794726736)

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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 RCV000180844 SCV000221809 pathogenic Severe myoclonic epilepsy in infancy 2014-12-20 criteria provided, single submitter research
GeneDx RCV000254957 SCV000321937 pathogenic not provided 2016-05-04 criteria provided, single submitter clinical testing The R580X nonsense variant in the SCN1A gene has been reported previously in association with SCN1A-related disorders (Depienne et al., 2009; SCN1A Variant Database). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Invitae RCV000544887 SCV000633815 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2017-06-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg580*) 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 in many individuals with Dravet syndrome (PMID: 18930999, 20522430, 20110217, 25206388, 24502503). ClinVar contains an entry for this variant (Variation ID: 189892). Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). For these reasons, this variant has been classified as Pathogenic.
LifeCell International Pvt. Ltd RCV000180844 SCV001739359 pathogenic Severe myoclonic epilepsy in infancy criteria provided, single submitter clinical testing A heterozygous nonsense variation in exon 14 of the SCN1A gene (c.1738C>T) that results in a stop codon and premature truncation of the protein at codon 580 (p.Arg580Ter) 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. 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.Arg580Ter 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.Met1Ile and 385 others. There are 254 downstream pathogenic loss of function variants, with the furthest variant being 1346 residues downstream of the variant p.Arg580Ter. This variant has previously been reported for seizure-related syndromes by Kong et al., 2019. Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines.

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