rs121917921

Positions:

• chr2-165991927-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.5348C>T​(p.Ala1783Val) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.93

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]

SCN1A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S6 of repeat IV (size 22) in uniprot entity SCN1A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.973
• PP5: Variant 2-165991927-G-A is Pathogenic according to our data. Variant chr2-165991927-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165991927-G-A is described in Lovd as [Pathogenic]. Variant chr2-165991927-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.5348C>T	p.Ala1783Val	missense_variant	29/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.5348C>T	p.Ala1783Val	missense_variant	29/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.5348C>T	p.Ala1783Val	missense_variant	28/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.5315C>T	p.Ala1772Val	missense_variant	26/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.5264C>T	p.Ala1755Val	missense_variant	26/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jun 26, 2023	PM1, PP3, PM5, PP2, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2024	A different missense change at this residue (p.A1755T) has been reported in the published literature and at GeneDx in association with SCN1A-related epilepsy (PMID: 20431604, 17347258); Published functional studies demonstrate that this variant significantly affects activation and slow inactivation properties of SCN1A NaV1.1 channels (PMID: 34776868); This substitution is predicted to be within the transmembrane segment S6 of the fourth homologous domain; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21703448, 29056246, 30368457, 32090326, 29573403, 33902251, 35074891, 30552426, 17561957, 34776868, 29460957, 20431604, 17347258) -

Severe myoclonic epilepsy in infancy Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1783 of the SCN1A protein (p.Ala1783Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 17561957, 18930999, 29460957). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68571). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D;D;.;.;.;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;.;M;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	.;.;.;D;.;D;.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;D;.;D;.;D;D
Sift4G	Benign	0.12	.;.;.;T;.;T;.;T;T
Polyphen		1.0	.;.;.;.;D;.;D;D;.
Vest4		0.95, 0.97, 0.97, 0.94
MutPred		0.83		.;.;.;Loss of helix (P = 0.2271);.;Loss of helix (P = 0.2271);.;.;.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121917921; hg19: chr2-166848437; COSMIC: COSV57658839; COSMIC: COSV57658839;