rs794726730
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001353961.2(SCN1A):c.-325C>T variant causes a 5 prime UTR premature start codon gain change. 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 (★★).
Frequency
Consequence
NM_001353961.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN1A | ENST00000674923.1 | c.2134C>T | p.Arg712* | stop_gained | Exon 15 of 29 | NM_001165963.4 | ENSP00000501589.1 | |||
| SCN1A | ENST00000303395.9 | c.2134C>T | p.Arg712* | stop_gained | Exon 14 of 28 | 5 | ENSP00000303540.4 | |||
| SCN1A | ENST00000375405.7 | c.2101C>T | p.Arg701* | stop_gained | Exon 12 of 26 | 5 | ENSP00000364554.3 | |||
| SCN1A | ENST00000409050.1 | c.2050C>T | p.Arg684* | stop_gained | Exon 12 of 26 | 5 | ENSP00000386312.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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: 16458823, 22151702, 18930999, 32056211, 23195492, 23808377, 20522430, 25525159, 26096185, 26188943, 25754450, 19585586, 28079314, 28387369, 29100083, 30641252, 29933521, 11940708, 31864146, 32090326, 32139178, 34489640, 34163418, 34055682, 32651551, 31031587, 35074891, 35886038, 35253369, 35571373, 34992632) -
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SCN1A: PS2:Very Strong, PVS1, PM2, PS4:Moderate -
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This variant has been identified in multiple unrelated individuals with Dravet syndrome and severe myoclonic epilepsy of infancy (SMEI) and has been confirmed to occur de novo in multiple individuals. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as R701X. -
Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:3
The c.2134C>T (p.Arg712Ter) stop gained variant in SCN1A gene has been reported previously in patients affected with Dravet syndrome in the de novo state (Wang et al., 2012), and in patients with epileptic encephalopathy (Ohimori et al., 2002). The p.Arg712Ter variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.2134C>T in SCN1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
A heterozygous nonsense variation in exon 15 of the SCN1A gene (c.2134C>T) that results in a stop codon and premature truncation of the protein at codon 712 (p.Arg712Ter) 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 CADD is damaging. The gene SCN1A has a low rate of benign loss of function variants as indicated by a high LoF variants Z-Score of 8.42. This variant is predicted to cause loss of normal protein function through protein truncation.This variant has previously been reported for early infantile epileptic encephalopathy by Arafat A et al., 2017. This variant was found in ClinVar (Variant 189886) with a classification of Pathogenic with respect to Early infantile epileptic encephalopathy with suppression bursts and a review status of (2 stars) no assertion criteria provided (https://www.ncbi.nlm.nih.gov/clinvar/variation/189886/). Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines. -
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Severe myoclonic epilepsy in infancy Pathogenic:3
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Criteria applied: PVS1,PS4_MOD,PM2_SUP -
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Autosomal dominant epilepsy Pathogenic:1
Variant summary: SCN1A c.2134C>T (p.Arg712X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251266 control chromosomes. c.2134C>T has been reported in the literature in individuals with Dravet syndrome in the de novo state (eg. Wang_2012), and in patients with epileptic encephalopathy (eg Sugawara_2002, Ohimori_2002). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Developmental and epileptic encephalopathy, 1 Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.2134C>T (p.R712*) alteration, located in exon 12 (coding exon 12) of the SCN1A gene, consists of a C to T substitution at nucleotide position 2134. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 712. Based on data from the Genome Aggregation Database (gnomAD), the SCN1A c.2134C>T alteration was not observed, with coverage at this position. This mutation has been detected in several individuals, in some cases as de novo occurrences, with Dravet syndrome, epileptic encephalopathy, severe intellectual disability, and non specific neurodevelopmental disorders (Gaily, 2013; Zhang, 2015; Do, 2017; Arafat, 2017; Hamdan, 2017; Froukh, 2020). The p.R712* alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189886). This premature translational stop signal has been observed in individual(s) with epileptic encephalopathy and Dravet syndrome (PMID: 11940708, 12083760, 18804930, 23195492, 23808377, 26544041). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg712*) 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
The SCN1A c.2134C>T variant is predicted to result in premature protein termination (p.Arg712*). This variant has been reported in many individuals with Dravet syndrome, and in several of these individuals, it occurred de novo (see, for example, Sugawara et al. 2002. PubMed ID: 11940708, reported as R701X; Table e-1, Zuberi et al. 2011. PubMed ID: 21248271; E-Table A, Wang et al. 2012. PubMed ID: 23195492). It has also been reported de novo in individuals with epileptic encephalopathy (Table S5, Hamdan et al. 2017. PubMed ID: 29100083; referred to as c.2050C>T, Sun et al. 2021. PubMed ID: 34055682). This variant has not been reported in a large population database, indicating it is rare. Nonsense variants in SCN1A are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at