rs121917937

chr2-166052866-A-Cchr2-166052866-A-G

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.680T>G(p.Ile227Ser) 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. I227T) has been classified as Likely 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:2
• Conservation: PhyloP100: 9.32

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 hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr2-166052866-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 930374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SCN1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 2-166052866-A-C is Pathogenic according to our data. Variant chr2-166052866-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 68579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.680T>G	p.Ile227Ser	missense_variant	8/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.680T>G	p.Ile227Ser	missense_variant	8/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+16736A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:2 Other:2

not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A heterozygous missense variant (c.680T>G) in exon 8 of the SCN1A gene that results in the amino acid substitution from Isoleucine to Serine at codon 227 (p.Ile227Ser) was identified. There is a large physicochemical difference between Isoleucine to Serine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. 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. This variant has previously been reported for Dravet syndrome by Huang W et al., 2017. This variant is a non-conservative amino acid substitution that alters a highly conserved position in the transmembrane segment S4 (voltage sensor) of the first homologous domain, and functional studies indicate that it significantly impairs channel function (Ohmori et al., 2006). This variant has been previously classified as Pathogenic in ClinVar (Variation ID 68579 as of 2019-08-05) with respect to Dravet syndrome with a status of (2 stars) criteria provided, multiple submitters, no conflicts. 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). Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2015	The I227S missense variant in the SCN1A gene has been reported previously as a de novo pathogenic variant in association with Dravet syndrome and other SCN1A-related disorders (Nabbout et al., 2003; Mancardi, et al., 2006; SCN1A Variant Database). This variant is a non-conservative amino acid substitution that alters a highly conserved position in the transmembrane segment S4 (voltage sensor) of the first homologous domain, and functional studies indicate that it significantly impairs channel function (Ohmori et al., 2006). Therefore, the presence of Ile227Ser is consistent with a diagnosis of an SCN1A related disorder -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2016	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2022

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. Experimental studies have shown that this missense change affects SCN1A function (PMID: 17054685). ClinVar contains an entry for this variant (Variation ID: 68579). This missense change has been observed in individual(s) with Dravet syndrome, severe myoclonic epilepsy of infancy, and/or unspecified epilepsy (PMID: 12821740, 17054684, 19589774, 22050978, 22147323, 23195492). 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 isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 227 of the SCN1A protein (p.Ile227Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
Polyphen		1.0, 0.92	.;.;D;P;.;D;P;P;.
Vest4		0.98, 0.95, 0.96
MutPred		0.87		Loss of stability (P = 0.0182);Loss of stability (P = 0.0182);Loss of stability (P = 0.0182);Loss of stability (P = 0.0182);Loss of stability (P = 0.0182);Loss of stability (P = 0.0182);Loss of stability (P = 0.0182);Loss of stability (P = 0.0182);Loss of stability (P = 0.0182);
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121917937; hg19: chr2-166909376;