rs121918626

Variant names:

• chr2-166012179-T-G
• rs121918626
• NM_001165963.4:c.3809A>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.3809A>C​(p.Lys1270Thr) 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. 13/22 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. K1270N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 8.02
• Publications: 27 publications found

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)

LOC102724058 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 9 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
• 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 familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 2-166012179-T-G is Pathogenic according to our data. Variant chr2-166012179-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 12891.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.3809A>C	p.Lys1270Thr	missense_variant	Exon 22 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3809A>C	p.Lys1270Thr	missense_variant	Exon 22 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.3809A>C	p.Lys1270Thr	missense_variant	Exon 21 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.3776A>C	p.Lys1259Thr	missense_variant	Exon 19 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.3725A>C	p.Lys1242Thr	missense_variant	Exon 21 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Feb 20, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3809A>C (p.K1270T) alteration is located in exon 19 (coding exon 19) of the SCN1A gene. This alteration results from a A to C substitution at nucleotide position 3809, causing the lysine (K) at amino acid position 1270 to be replaced by a threonine (T). for autosomal dominant SCN1A-related seizure disorders; however, its clinical significance for autosomal dominant SCN1A-related hemiplegic migraine is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was identified in one or more individuals with features consistent with SCN1A-related seizure disorders and segregated with disease in at least one family (Abou-Khalil, 2001). This amino acid position is highly conserved in available vertebrate species. Animal models expressing this variant exhibited phenotype(s) consistent with SCN1A-related seizure disorders (Das, 2021; Sun, 2012; Schutte, 2014). In multiple assays testing SCN1A function, this variant showed functionally abnormal results (Xie, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Developmental and epileptic encephalopathy Pathogenic:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1270 of the SCN1A protein (p.Lys1270Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with generalized epilepsy with febrile seizures plus (GEFS+) (PMID: 11756608). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12891). 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%. For these reasons, this variant has been classified as Pathogenic. -

Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:1

Dec 26, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Generalized epilepsy with febrile seizures plus, type 1 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	5.7	.;.;.;H;.;.;H;.;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.8	.;.;.;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, 0.96	.;.;.;D;D;.;D;D;D;.
Vest4		0.96, 0.98, 0.97, 0.96
MutPred		0.69		.;Loss of methylation at K1270 (P = 0.0175);.;Loss of methylation at K1270 (P = 0.0175);.;.;Loss of methylation at K1270 (P = 0.0175);.;.;.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918626; hg19: chr2-166868689;