2-166002588-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001165963.4(SCN1A):c.4168G>A(p.Val1390Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 2.70

Variant links:

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 links:

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

SCN1A-AS1 links:

LOC102724058 (HGNC:):

LOC102724058 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a topological_domain Extracellular (size 51) in uniprot entity SCN1A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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 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, 0.873

PP5

Variant 2-166002588-C-T is Pathogenic according to our data. Variant chr2-166002588-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166002588-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.4168G>A	p.Val1390Met	missense_variant	Exon 24 of 29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.4168G>A	p.Val1390Met	missense_variant	Exon 24 of 29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.4168G>A	p.Val1390Met	missense_variant	Exon 23 of 28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.4135G>A	p.Val1379Met	missense_variant	Exon 21 of 26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 link	c.4084G>A	p.Val1362Met	missense_variant	Exon 21 of 26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 15, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the third homologous domain; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20431604, 26096185, 31864146, 12083760, 17347258, 15277629, 22780858, 31879226, 29141279, 33108073, 23762420, 31031587, 18804930) -

Severe myoclonic epilepsy in infancy

Pathogenic:2Other:1

Feb 08, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS4_MOD, PM5, PM1_SUP, PM2_SUP,PP2, PP3 -

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 20, 2014

Center for Bioinformatics, Peking University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Inborn genetic diseases

Pathogenic:1

Jun 20, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1390M variant (also known as c.4168G>A), located in coding exon 21 of the SCN1A gene, results from a G to A substitution at nucleotide position 4168. The valine at codon 1390 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in several individuals with clinical diagnoses of Dravet syndrome (Aljaafari D et al. Epilepsia, 2017 03;58:e44-e48; Rilstone JJ et al. Epilepsia, 2012 Aug;53:1421-8; Cho MJ et al. J Clin Neurol, 2018 Jan;14:22-28) and as a de novo occurrence in an individual with borderline severe myoclonic epilepsy of infancy (SMEI) (Sun H et al. Epilepsia, 2008 Jun;49:1104-7). In addition, a different alteration located at the same position, p.V1390L (c.4168G>T), has been detected in an individual with Dravet syndrome and co-segregated with disease in a family with a variable epilepsy phenotype (Tian X et al. Dev Med Child Neurol, 2018 06;60:566-573; Mhanni AA et al. Seizure, 2011 Nov;20:711-2). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1390 of the SCN1A protein (p.Val1390Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 12083760, 20431604, 22780858, 23762420, 29141279, 30182498). In at least one individual the variant was observed to be de novo. This variant is also known as c.A3169G p.V1380M. ClinVar contains an entry for this variant (Variation ID: 68537). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;.;D;.;.;D;.;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D;D;.;D;.;.;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

.;.;H;.;.;H;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

.;.;D;.;.;D;.;D;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

.;.;D;.;.;D;.;D;D

Sift4G

Pathogenic

0.0010

.;.;D;.;.;D;.;D;D

Polyphen

0.97, 0.90

.;.;D;P;.;D;P;P;.

Vest4

0.59, 0.81, 0.71, 0.64

MutPred

0.53

.;.;Gain of disorder (P = 0.0636);.;.;Gain of disorder (P = 0.0636);.;.;.;

MVP

1.0

MPC

1.7

ClinPred

0.98

GERP RS

5.5

Varity_R

0.37

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over