2-166037885-C-T

Variant names:

• chr2-166037885-C-T
• rs121917971
• NM_001165963.4:c.2837G>A

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.2837G>A​(p.Arg946His) 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. 14/22 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. R946S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 7.90
• Publications: 13 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)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 29 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 chr2-166037886-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 68604.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, 0.962
• PP5: Variant 2-166037885-C-T is Pathogenic according to our data. Variant chr2-166037885-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68523.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.2837G>A	p.Arg946His	missense	Exon 18 of 29	NP_001159435.1
	SCN1A	NM_001202435.3		c.2837G>A	p.Arg946His	missense	Exon 17 of 28	NP_001189364.1
	SCN1A	NM_001353948.2		c.2837G>A	p.Arg946His	missense	Exon 16 of 27	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.2837G>A	p.Arg946His	missense	Exon 18 of 29	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.2837G>A	p.Arg946His	missense	Exon 17 of 28	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.2804G>A	p.Arg935His	missense	Exon 15 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Feb 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest that R946H results in complete loss of function of the Nav1.1 protein (Liao et al., 2010; Volkers et al., 2011); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This substitution is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the second homologous domain; This variant is associated with the following publications: (PMID: 15508916, 18930999, 15277629, 16713920, 17347258, 16713913, 21371021, 17166794, 20550552, 14738421, 23195492, 21864321, 27781031, 19589774, 28492532, 15944908, 31780880, 32090326, 33851778)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Severe myoclonic epilepsy in infancy Pathogenic:2 Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jun 26, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SCN1A c.2837G>A (p.Arg946His) variant involves the alteration of a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Histidine (H) located in the in the pore loop region of the SCN1A gene. 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121408 control chromosomes while it was reported in several Dravet Syndrome patients, some of whom the variant arose de novo, strongly indicating causality. Moreover, independent functional studies reported the variant to result in absent measurable sodium currents, further supporting pathogenicity. In addition, mutations affecting the same codon have been described as pathogenic (c.2837G>A, p.R946P; c.2836C>A, p.R946S; c.2836C>T, p.R946C; HGMD, ClinVar) underscoring the functional/clinical importance of the R946 residue and indicating the variant to be located in a mutation hotspot. Furthermore, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Developmental and epileptic encephalopathy 6B Pathogenic:2

Nov 22, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant (also known as R936H in the literature) was previously reported in several individuals with SCN1A-related epilepsy [PMID: 21864321, 27781031, 23195492, 21371021]. Functional studies have suggested that this variant results in complete loss of SCN1A function in cell culture [PMID: 21864321, 20550552]. In addition, missense variants affecting the same codon of the identified variant (p.R946S; p.R946C) have been reported to be pathogenic [PMID: 21864321, 14738421, 15944908].

Aug 23, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PS4,PM1,PM2,PM5,PP3_MOD

Inborn genetic diseases Pathogenic:1

Dec 14, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R946H variant (also known as c.2837G>A), located in coding exon 15 of the SCN1A gene, results from a G to A substitution at nucleotide position 2837. The arginine at codon 946 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in multiple individuals with seizure disorders, including Dravet syndrome, severe myoclonic epilepsy in infancy, and generalized epilepsy with febrile seizures plus (GEFS+), occurring both de novo as well as inherited (Harkin LA et al. Brain, 2007 Mar;130:843-52; Depienne C et al. J. Med. Genet., 2009 Mar;46:183-91; Liao WP et al. Epilepsia, 2010 Sep;51:1669-78; Zuberi SM et al. Neurology, 2011 Feb;76:594-600; Verbeek NE et al. Epilepsia, 2011 Apr;52:e23-5; Volkers L et al. Eur. J. Neurosci., 2011 Oct;34:1268-75; Wang JW et al. Epilepsy Res., 2012 Dec;102:195-200; Møller RS et al. Mol Syndromol, 2016 Sep;7:210-219). In addition, when transfected into tsA201 cells, this variant demonstrated no measurable sodium currents when expressed heterologously with the recombinant human accessory sodium channel subunits β1 and β2 (Liao WP et al. Epilepsia, 2010 Sep;51:1669-78; Volkers L et al. Eur. J. Neurosci., 2011 Oct;34:1268-75). This amino acid position is highly 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 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 946 of the SCN1A protein (p.Arg946His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SCN1A-related epilepsy (PMID: 14738421, 19589774, 20550552, 21371021, 21864321, 23195492, 27781031). In at least one individual the variant was observed to be de novo. This variant is also known as R936H. ClinVar contains an entry for this variant (Variation ID: 68523). 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: 20550552, 21864321). This variant disrupts the p.Arg946 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14738421, 21864321). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Aug 22, 2018

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Seizure Pathogenic:1

Nov 10, 2020

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Missense variant predicted pathogenic by bioinformatic scores. Absent from gnomAD but recurrent in the literature.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.80		Gain of sheet (P = 0.1208)
MVP		1.0
MPC		3.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.96
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: rs121917971; hg19: chr2-166894395;