chr2-166039436-C-T

Position:

chr2-166039436-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6U:1O:1

Conservation

PhyloP100: 7.90

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a repeat II (size 272) in uniprot entity SCN1A_HUMAN there are 49 pathogenic changes around while only 2 benign (96%) in NM_001165963.4

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). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. GenCC has associacion of the 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, 0.981

PP5

Variant 2-166039436-C-T is Pathogenic according to our data. Variant chr2-166039436-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 93639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166039436-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.2576G>A	p.Arg859His	missense_variant	17/29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.2576G>A	p.Arg859His	missense_variant	17/29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.2576G>A	p.Arg859His	missense_variant	16/28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.2543G>A	p.Arg848His	missense_variant	14/26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 link	c.2492G>A	p.Arg831His	missense_variant	14/26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250370

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135346

show subpopulations

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 SAS 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:

AN:

1453400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723412

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 01, 2013	- -

Autosomal dominant epilepsy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 23, 2020

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. -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2023

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. -

Generalized epilepsy with febrile seizures plus, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

SCN1A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

- -

Severe myoclonic epilepsy in infancy

Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.7

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

PrimateAI

Pathogenic

0.82

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

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.99

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

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