rs1553525325

Variant names:

• chr2-166002716-A-G
• rs1553525325
• NM_001165963.4:c.4040T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-166002716-A-G
• chr2-166002716-A-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.4040T>C​(p.Ile1347Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1347V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32
• Publications: 1 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 19 ACMG points.

• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr2-166002717-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2775809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.947
• PP5: Variant 2-166002716-A-G is Pathogenic according to our data. Variant chr2-166002716-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 851568.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.4040T>C	p.Ile1347Thr	missense_variant	Exon 24 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4040T>C	p.Ile1347Thr	missense_variant	Exon 24 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4040T>C	p.Ile1347Thr	missense_variant	Exon 23 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4007T>C	p.Ile1336Thr	missense_variant	Exon 21 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.3956T>C	p.Ile1319Thr	missense_variant	Exon 23 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This substitution is predicted to be within the transmembrane segment S5 of the third homologous domain; 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: 27652284) -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN1A: PS2, PM1, PM2, PP3, PS4:Supporting -

Developmental and epileptic encephalopathy Pathogenic:1

Jul 01, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with threonine at codon 1347 of the SCN1A protein (p.Ile1347Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with SCN1A-related epilepsy (PMID: 27652284, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	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
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	.;.;H;.;.;H;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.8	.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.053	.;.;T;.;.;T;.;T;T
Polyphen		1.0, 0.99	.;.;D;D;.;D;D;D;.
Vest4		0.96, 0.99, 0.99, 0.98
MutPred		0.70		.;.;Gain of catalytic residue at I1347 (P = 0.0107);.;.;Gain of catalytic residue at I1347 (P = 0.0107);.;.;.;
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.82
gMVP		0.97
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: rs1553525325; hg19: chr2-166859226;