rs1057523858
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001165963.4(SCN1A):c.1150T>A(p.Trp384Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W384S) has been classified as Pathogenic.
Frequency
Consequence
NM_001165963.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 23 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.1150T>A | p.Trp384Arg | missense_variant | 11/29 | ENST00000674923.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.1150T>A | p.Trp384Arg | missense_variant | 11/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.487+11517A>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2017 | This sequence change replaces tryptophan with arginine at codon 384 of the SCN1A protein (p.Trp384Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant identified in the SCN1A gene is located in the extracellular D1-P1 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. For these reasons, this variant has been classified as Pathogenic. A different variant (c.1150T>C) giving rise to the same protein effect observed here (p.Trp384Arg) has been reported to be de novo in individuals affected with Dravet syndrome (PMID: 23195492, 21248271), indicating that this residue may be critical for protein function. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to be de novo in an individual affected with Dravet Syndrome and vaccination induced seizures (PMID: 23762420). ClinVar contains an entry for this variant (Variation ID: 390676). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2019 | Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This substitution is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the first homologous domain; This variant is associated with the following publications: (PMID: 30619928, 23762420, 23195492, 18804930, 31009440) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at