rs121917984
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001165963.4(SCN1A):c.677C>T(p.Thr226Met) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T226R) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
SCN1A
NM_001165963.4 missense
NM_001165963.4 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001165963.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-166052869-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 206930.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN1A. . Gene score misZ 5.2206 (greater than the threshold 3.09). Trascript score misZ 7.6022 (greater than threshold 3.09). GenCC has associacion of gene with migraine, familial hemiplegic, 3, familial hemiplegic migraine, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, myoclonic-astatic epilepsy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 6, familial or sporadic hemiplegic migraine, arthrogryposis, Lennox-Gastaut syndrome, generalized epilepsy with febrile seizures plus, type 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947
PP5
Variant 2-166052869-G-A is Pathogenic according to our data. Variant chr2-166052869-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166052869-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SCN1A | NM_001165963.4 | c.677C>T | p.Thr226Met | missense_variant | 8/29 | ENST00000674923.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SCN1A | ENST00000674923.1 | c.677C>T | p.Thr226Met | missense_variant | 8/29 | NM_001165963.4 | P4 | ||
| SCN1A-AS1 | ENST00000651574.1 | n.487+16739G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | SCN1A: PS2, PM2, PM5, PS4:Moderate, PP2, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2022 | Published functional studies demonstrate a damaging effect (Berecki et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 17347258, 23895530, 21719429, 19585586, 18804930, 25401298, 28794249, 25741868, 30779207, 31791873, 32581362, 31785789, 34489640, 33084218, 31130284, 28252636, 31257984, 31864146) - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Severe myoclonic epilepsy in infancy Pathogenic:2Other:2
| not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
| not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2018 | This variant was identified as de novo (maternity and paternity confirmed). - |
Developmental and epileptic encephalopathy 6B Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 19, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2007 | - - |
Seizure;C0557874:Global developmental delay Pathogenic:1
| Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Developmental and epileptic encephalopathy, 6 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0200 Variant is predicted to result in a missense amino acid change from threonine to methionine (exon 5). (N) 0251 Variant is heterozygous. (N) 0107 This gene is known to be associated with autosomal dominant disease. (N) 0301 Variant is absent from gnomAD. (P) 0801 Strong previous evidence of pathogenicity in unrelated individuals (ClinVar; LOVD; Decipher; Berecki, G. et al. (2019)). (P) 0600 Variant is located in an annotated domain or motif (ion transport domain; NCBI, PDB, Decipher). (N) 0501 Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0103 Both loss- and gain-of-function are known mechanisms of disease for this gene (Wei, F. et al. (2017)). (N) 1204 Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 09, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 226 of the SCN1A protein (p.Thr226Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome and cryptogenic generalized epilepsy (PMID: 17347258, 23895530, 25401298). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68578). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. For these reasons, this variant has been classified as Pathogenic. - |
Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | - | A heterozygous missense variation in exon 7 of the SCN1A gene that results in the amino acid substitution of Methionine for Threonine at codon 226 was detected. The observed variant c.677C>T (p.Thr226Met) has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. - |
Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;D;.;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;.;M;M;.;M;M;M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;.;D;.;.;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;.;D;.;.;D;.;D;D
Sift4G
Pathogenic
.;.;D;.;.;D;.;D;D
Polyphen
1.0
.;.;D;D;.;D;D;D;.
Vest4
0.90, 0.95, 0.95, 0.91
MutPred
Gain of MoRF binding (P = 0.1037);Gain of MoRF binding (P = 0.1037);Gain of MoRF binding (P = 0.1037);Gain of MoRF binding (P = 0.1037);Gain of MoRF binding (P = 0.1037);Gain of MoRF binding (P = 0.1037);Gain of MoRF binding (P = 0.1037);Gain of MoRF binding (P = 0.1037);Gain of MoRF binding (P = 0.1037);
MVP
1.0
MPC
1.7
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at