ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.2556+3A>T (rs794726775)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Bioinformatics, Peking University RCV000180891 SCV000221863 pathogenic Severe myoclonic epilepsy in infancy 2014-12-20 criteria provided, single submitter research
GeneDx RCV000188876 SCV000242506 pathogenic not provided 2017-07-26 criteria provided, single submitter clinical testing The c.2589+3 A>T splice site variant in the SCN1A gene has been previously reported as a de novo pathogenic variant associated with Dravet syndrome in the literature (Harkin et al., 2007; Liu et al., 2013) and in another individual from a different family tested previously at GeneDx. RNA and protein studies have shown that this variant destroys the splice donor site in intron 14, leading to the skipping of exon 14 and resulting in greatly reduced protein levels in heterologous expression systems. Functional studies using induced neurons derived from patient cells indicated that this variant caused increased sodium current density, resulting in cell death (Liu et al, 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The presence of c.2589+3 A>T is consistent with a diagnosis of a SCN1A-related disorder
Athena Diagnostics Inc RCV000180891 SCV000255817 pathogenic Severe myoclonic epilepsy in infancy 2014-12-26 criteria provided, single submitter clinical testing
Invitae RCV000554065 SCV000633830 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-05-26 criteria provided, single submitter clinical testing This sequence change falls in an intron of the SCN1A gene. While it does not directly change the encoded amino acid sequence of the SCN1A protein, it is located within the consensus donor splice site for exon 14. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals with severe myoclonic epilepsy of infancy (SMEI) or intractable seizures (PMID: 17347258, 23821540, 23195492). In at least two of these individuals, this variant was found to be absent from both parents and presumed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189938). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This particular variant has been shown to result in skipping of exon 14 during splicing of the SCN1A gene, which correlates with a little to no SCN1A protein expression and no sodium current in a heterologous system (PMID: 23195492). In summary, this variant is a rare splice site variant that has been shown to disrupt mRNA splicing and protein function. It is also absent from the general population and present in several individuals affected with SCN1A-related disease. For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000180891 SCV000677106 pathogenic Severe myoclonic epilepsy in infancy 2017-11-09 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188876 SCV001248482 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
LifeCell International Pvt. Ltd RCV000180891 SCV001739360 pathogenic Severe myoclonic epilepsy in infancy criteria provided, single submitter clinical testing A heterozygous 5’ splice site variation in intron 17 of the SCN1A gene (c.2589+3A>T) that affects the position 3 bases downstream of exon 17 was detected. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Mutation taster, NNSplice and PWM are damaging. This variant (also known as IVS14+3A>T) has previously been reported for Dravet syndrome by Xu X. et al., 2015. This variant has been shown to result in skipping of exon 17 during splicing of the SCN1A gene, which correlates with a little to no SCN1A protein expression and no sodium current in a heterologous system by Liu Y. et al., 2013. The variant c.2589+3A>T has been previously classified as Pathogenic in ClinVar (Variation ID 189938 as of 2020-09-03) 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000188876 SCV001741377 pathogenic not provided no assertion criteria provided clinical testing

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