rs121917937

Variant names:

• chr2-166052866-A-C
• rs121917937
• NM_001165963.4:c.680T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-166052866-A-C
• chr2-166052866-A-G
• chr2-166052866-A-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.984
• 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 rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.680T>G	p.Ile227Ser	missense_variant	Exon 8 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.680T>G	p.Ile227Ser	missense_variant	Exon 8 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.680T>G	p.Ile227Ser	missense_variant	Exon 7 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.680T>G	p.Ile227Ser	missense_variant	Exon 5 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.680T>G	p.Ile227Ser	missense_variant	Exon 5 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:3 Other:2

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 20, 2014

Center for Bioinformatics, Peking University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Jan 25, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17054685). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 1.00 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068579 / PMID: 12821740). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 17054684). A different missense change at the same codon (p.Ile227Thr) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000930374). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Dec 24, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Apr 04, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 68579). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN1A function (PMID: 17054685). For these reasons, this variant has been classified as Pathogenic. -

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
DEOGEN2	Pathogenic	0.99	.;.;D;.;.;D;.;.;.
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
MutationAssessor	Pathogenic	4.4	.;.;H;H;.;H;H;H;H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.9	.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0030	.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;.;.;D;.;D;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;