rs121917965

Positions:

• chr2-166058652-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.301C>T​(p.Arg101Trp) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R101Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.93

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-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 127) in uniprot entity SCN1A_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) 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 chr2-166058651-C-T is described in Lovd as [Pathogenic].
• 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 2-166058652-G-A is Pathogenic according to our data. Variant chr2-166058652-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166058652-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.301C>T	p.Arg101Trp	missense_variant	5/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.301C>T	p.Arg101Trp	missense_variant	5/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.488-16636G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A heterozygous missense variant (c.301C>T) in exon 5 of the SCN1A gene that results in the amino acid substitution from Arginine to Tryptophan at codon 101 (p.Arg101Trp) was identified. There is a moderate physicochemical difference between Arginine and Tryptophan. 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 Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 5.61. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). This variant has previously been reported for Dravet syndrome by Usluer S et al., 2016. This variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 68527 as of 2020-06-04). Based on the above evidence this variant has been classified as Likely pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 30, 2024	Criteria applied: PM5_STR,PS2_MOD,PS4_MOD,PM2_SUP,PP2,PP3 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2022	This substitution is predicted to be within the N-terminal cytoplasmic domain; Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19585586, 20431604, 26096185, 27113213, 27236449, 29933521, 17347258, 18930999, 29852413, 30619928, 31164858, 31864146, 32090326, 29573403, 33278787, 31031587) -

Migraine, familial hemiplegic, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 06, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3,PM2,PM1. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 27, 2023

This variant disrupts the p.Arg101 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20431604, 23195492, 23808377, 24328833, 25885068). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 68527). This missense change has been observed in individual(s) with severe myoclonic epilepsyof infancy (SMEI) and Dravet Syndrome (PMID: 17347258, 20431604, 24168886, 27113213, 27236449). 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 replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 101 of the SCN1A protein (p.Arg101Trp). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;.;.;H;H;.;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.1	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0	.;.;.;.;D;.;.;D;D;.
Vest4		0.94, 0.95, 0.95, 0.96
MutPred		0.72		Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs121917965; hg19: chr2-166915162;