2-166002588-C-T

Variant names:

• chr2-166002588-C-T
• rs121917986
• NM_001165963.4:c.4168G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1390L) 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:9 O:1
• Conservation: PhyloP100: 2.70
• Publications: 18 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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 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 chr2-166002588-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2734302.Status of the report is criteria_provided_single_submitter, 1 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, 0.873
• PP5: Variant 2-166002588-C-T is Pathogenic according to our data. Variant chr2-166002588-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.4168G>A	p.Val1390Met	missense	Exon 24 of 29	NP_001159435.1
	SCN1A	NM_001202435.3		c.4168G>A	p.Val1390Met	missense	Exon 23 of 28	NP_001189364.1
	SCN1A	NM_001353948.2		c.4168G>A	p.Val1390Met	missense	Exon 22 of 27	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.4168G>A	p.Val1390Met	missense	Exon 24 of 29	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.4168G>A	p.Val1390Met	missense	Exon 23 of 28	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.4135G>A	p.Val1379Met	missense	Exon 21 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:4 Other:1

Dec 20, 2014

Center for Bioinformatics, Peking University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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

Sep 13, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.0.0 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.74 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068537 /PMID: 12083760). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 30182498). Different missense changes at the same codon (p.Val1390Ala, p.Val1390Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000190014, VCV002107915, VCV002734302 /PMID: 21775168). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Dec 26, 2024

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:3

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)

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Developmental and epileptic encephalopathy 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.97	D
Vest4		0.59
MutPred		0.53		Gain of disorder (P = 0.0636)
MVP		1.0
MPC		1.7
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.37
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121917986; hg19: chr2-166859098; COSMIC: COSV57666805; COSMIC: COSV57666805;