rs794726736
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001165963.4(SCN1A):c.1738C>T(p.Arg580Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R580R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001165963.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.1738C>T | p.Arg580Ter | stop_gained | 14/29 | ENST00000674923.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.1738C>T | p.Arg580Ter | stop_gained | 14/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.487+7844G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Severe myoclonic epilepsy in infancy Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Center for Bioinformatics, Peking University | Dec 20, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 09, 2023 | Criteria applied: PVS1,PS4,PM2_SUP,PS2 - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 10, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2023 | Identified in siblings with Dravet syndrome and seizures with possible maternal mosaicism in published literature (Depienne et al., 2010); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30945278, 25525159, 22151702, 24502503, 25754450, 30368457, 30619928, 31864146, 32090326, 34055682, 35074891, 34145886, 31440721, 25206388, 20110217, 26096185, 18930999, 20522430) - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189892). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 18930999, 20110217, 20522430, 24502503, 25206388). This variant is not present in population databases (gnomAD no frequency). 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. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). - |
SCN1A-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 11, 2023 | The SCN1A c.1738C>T variant is predicted to result in premature protein termination (p.Arg580*). This variant has been reported in multiple individuals with epilepsy/Dravet syndrome; in at least two patients it was reported to have occurred de novo, and in a third it was described as an inherited variant that was not detectable in the parents, suggesting parental germline mosaicism (Depienne et al. 2009. PubMed ID: 18930999; Takayama et al. 2014. PubMed ID: 24502503; Kong et al. 2018. PubMed ID: 30619928; Jiao et al. 2019. PubMed ID: 30945278). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Nonsense variants in SCN1A are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at