2-166039436-C-T

Variant names:

• chr2-166039436-C-T
• rs398123588
• NM_001165963.4:c.2576G>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.2576G>A​(p.Arg859His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,400 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R859C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.90
• Publications: 19 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 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr2-166039437-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 68592.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, 0.981
• PP5: Variant 2-166039436-C-T is Pathogenic according to our data. Variant chr2-166039436-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 93639.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.2576G>A	p.Arg859His	missense_variant	Exon 17 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2576G>A	p.Arg859His	missense_variant	Exon 17 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2576G>A	p.Arg859His	missense_variant	Exon 16 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2543G>A	p.Arg848His	missense_variant	Exon 14 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.2492G>A	p.Arg831His	missense_variant	Exon 16 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250370 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453400 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 723412

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5420

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105454

Other (OTH) AF: 0.00 AC: 0 AN: 60014

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 09, 2025

Department of Neurology, Zibo Changguo Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2_Very Strong, PS3, PM2_Supporting -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Apr 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest that p.R859H results in channel gating defects (Volkers et al., 2011; Volkers et al., 2013); Reported previously in an individual with generalized epilepsy with febrile seizures plus and was inherited from the patient's father who had a history of febrile seizures (Volkers et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 31782251, 29335582, 32581296, 28084635, 21864321, 33278787, 24277604, 28150151, 30446648, 33013363) -

Jul 01, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant epilepsy Pathogenic:1

Dec 23, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN1A c.2576G>A (p.Arg859His) results in a non-conservative amino acid change located in the Ion transport domain (voltage sensing S4 segment of domain II) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Another missense variant affecting the same codon, namely c.2575C>T (p.Arg859Cys) has been reported with the more severe phenotype of Dravet syndrome with loss of function effects suggesting a functional relevance of this residue to protein function (Brunklaus_2020). The variant allele was found at a frequency of 8e-06 in 250370 control chromosomes. c.2576G>A has been reported in the literature in at least 3 patients with Generalized Epilepsy with Febrile Seizures Plus (GEFS+). One report showing segregation within a family, though the affected father was not genotyped (Volkers_2011) and another reporting the variant as a de novo occurrence (Myers_2017). It has also been subsequently cited by others (example, Brunklaus_2020). Additionally, a clinical lab has submitted data to Clinvar stating that the variant segregated with seizures in a single family. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect leads to mixed functional defects in Nav1.1 gating although the mutant protein is produced at normal levels (Volkers_2011; Volkers_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Developmental and epileptic encephalopathy Pathogenic:1

May 20, 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 859 of the SCN1A protein (p.Arg859His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with generalized epilepsy with febrile seizures plus (PMID: 21864321, 28084635; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 93639). 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: 21864321, 24277604). This variant disrupts the p.Arg859 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16525050, 18930999, 25576396). 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. -

SCN1A-related disorder Pathogenic:1

Jun 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN1A c.2576G>A variant is predicted to result in the amino acid substitution p.Arg859His. This variant has been reported in multiple individuals with generalized epilepsy with febrile seizures plus (GEFS+) and has been repeatedly documented as having arisen de novo (Volkers et al. 2011. PubMed ID: 21864321; Myers et al. 2017. PubMed ID: 28084635; Wang et al. 2021. PubMed ID: 33278787; Zou et al. 2021. PubMed ID: 34145886; Chen et al. 2022. PubMed ID: 35571373; Çapan et al. 2023. PubMed ID: 37353388). In vitro functional studies have shown that this variant negatively impacts sodium channel function (Volkers et al. 2011. PubMed ID: 21864321; Volkers et al. 2013. PubMed ID: 24277604). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. A different missense variant at the same position (p.Arg859Cys) has also been reported as pathogenic in patients with SCN1A-related disease (Barela et al. 2006. PubMed ID: 16525050; Depienne et al. 2009. PubMed ID: 18930999; Bechi et al. 2015. PubMed ID: 25576396). Taken together, the p.Arg859His variant is interpreted as pathogenic. -

Seizure Uncertain:1

-

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.7	.;.;.;H;.;.;H;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.0070	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 1.0	.;.;.;D;D;.;D;D;D;.
Vest4		0.98, 0.99, 0.99, 0.99
MutPred		0.86		.;Loss of MoRF binding (P = 0.0338);.;Loss of MoRF binding (P = 0.0338);.;.;Loss of MoRF binding (P = 0.0338);.;.;.;
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.99
Mutation Taster		=1/99	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: rs398123588; hg19: chr2-166895946;