2-166046969-C-T

Position:

• chr2-166046969-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.1178G>A​(p.Arg393His) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:2
• Conservation: PhyloP100: 7.90

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

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN1A. . Gene score misZ 5.2206 (greater than the threshold 3.09). Trascript score misZ 7.6022 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.929
• PP5: Variant 2-166046969-C-T is Pathogenic according to our data. Variant chr2-166046969-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166046969-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1178G>A	p.Arg393His	missense_variant	12/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1178G>A	p.Arg393His	missense_variant	12/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.487+10839C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:5 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 10, 2024	Criteria applied: PS2_VSTR,PS3,PS4,PM5_STR,PM1,PM2_SUP -
Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2016	Variant summary: The SCN1A c.1178G>A variant affects a conserved nucleotide, resulting in amino acid change from a large and basic Arg to a medium sized and polar His residue at codon 393. This variant is present in S5S6 linker region of the protein which forms the pore of the protein (Rilstone_2012). 4/4 in-silico tool predict a damaging outcome for this variant. Another pathogenic variant p.Arg393Cys has also been reported in this codon, suggesting that the p.Arg393 is important for protein function. Whole-cell patch-clamp studies of R393H show no measurable sodium channel activity, suggesting that this missense change results in a loss of function. This variant was found in 1/121376 control chromosomes including broad and large populations from ExAC at a frequency of 0.0000082, which is lower than the maximal expected frequency of a pathogenic SCN1A allele (0.0000179). The variant has been reported in at least 8 SMEI unrelated patients in literature across various ethnicities, and in one patient with SMEB and one with intractable childhood epilepsy. The variant has also been reported to originate do novo, strongly supporting for a pathogenic outcome. In addition, multiple clinical laboratories have classified this variant as pathogenic. Taken together, this variant was classified as Disease Variant/Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R393H in SCN1A (NM_001165963.4) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported in additional individuals affected with SMEI, severe myoclonic epilepsy of infancy, borderline phenotype (SMEB) and Dravet syndrome (Wang JW et al, 2012; Rilstone JJ et al, 2012; Le SV, 2017). Experimental studies have shown that this missense change results in a non-functional SCN1A protein channel (Ohmori I et al, 2006). The p.R393H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R393H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 393 of SCN1A is conserved in all mammalian species. The nucleotide c.1178 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 26, 2022	This variant has been identified in multiple unrelated individuals with Dravet Syndrome. This variant has also been confirmed to occur de novo in multiple individuals. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 17054685. The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	Published functional studies demonstrate that R393H significantly impairs channel function (Ohmori et al., 2006); The majority of missense variants in this gene are considered pathogenic (HGMD); This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first homologous domain; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31782251, 30368457, 33067208, 34268891, 23195492, 17054685, 22780858, 26096185, 22612257, 20431604, 21248271, 28544625, 29720203, 32090326, 29738522, 34163418, 32613771, 33084218, 12754708) -

Migraine, familial hemiplegic, 3 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Center of Excellence for Medical Genomics, Chulalongkorn University	Sep 08, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jun 22, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP2,PP3,PP5. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 393 of the SCN1A protein (p.Arg393His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SMEI, severe myoclonic epilepsy of infancy, borderline phenotype (SMEB) and Dravet syndrome and severe myoclonic epilepsy of infancy (SMEI) (PMID: 12754708, 22780858, 23195492, 28544625). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68506). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 17054685). This variant disrupts the p.Arg393 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17054684, 21868258, 23934111). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;.;.;M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.058	.;.;.;T;.;.;T;.;T;T
Polyphen		1.0, 0.95	.;.;.;D;P;.;D;P;P;.
Vest4		0.91, 0.95, 0.94, 0.91
MutPred		0.67		Gain of methylation at K397 (P = 0.0778);Gain of methylation at K397 (P = 0.0778);Gain of methylation at K397 (P = 0.0778);Gain of methylation at K397 (P = 0.0778);Gain of methylation at K397 (P = 0.0778);Gain of methylation at K397 (P = 0.0778);Gain of methylation at K397 (P = 0.0778);Gain of methylation at K397 (P = 0.0778);Gain of methylation at K397 (P = 0.0778);Gain of methylation at K397 (P = 0.0778);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs121917927; hg19: chr2-166903479;