2-166039437-G-A

Variant names:

• chr2-166039437-G-A
• rs121918784
• NM_001165963.4:c.2575C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.2575C>T​(p.Arg859Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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. R859H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.45
• Publications: 14 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 17 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001165963.4
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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, 0.984
• PP5: Variant 2-166039437-G-A is Pathogenic according to our data. Variant chr2-166039437-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68592.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.2575C>T	p.Arg859Cys	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.2575C>T	p.Arg859Cys	missense_variant	Exon 17 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2575C>T	p.Arg859Cys	missense_variant	Exon 16 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2542C>T	p.Arg848Cys	missense_variant	Exon 14 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.2491C>T	p.Arg831Cys	missense_variant	Exon 16 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149732 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1459694 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 726182

⚠️ 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: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110504

Other (OTH) AF: 0.00 AC: 0 AN: 60310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000668 AC: 1 AN: 149732 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72854

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

African (AFR) AF: 0.00 AC: 0 AN: 40710

American (AMR) AF: 0.00 AC: 0 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67678

Other (OTH) AF: 0.00 AC: 0 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:3

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068592 / PMID: 16525050). Different missense changes at the same codon (p.Arg859His, p.Arg859Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093639 / PMID: 21864321, 29141311). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy Pathogenic:1

May 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 cysteine, which is neutral and slightly polar, at codon 859 of the SCN1A protein (p.Arg859Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome or generalized epilepsy with febrile seizures (PMID: 16525050, 18930999). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68592). 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: 16525050, 25576396). 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: 21864321, 24277604, 28084635; Invitae). 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. -

not provided Pathogenic:1

Oct 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate reduced neuronal excitability (PMID: 16525050); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25576396, 20831750, 20100831, 17304347, 25754450, 19292758, 35074891, 32090326, 18930999, 16525050) -

Severe myoclonic epilepsy in infancy Pathogenic:1

Aug 05, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizure Pathogenic:1

Mar 25, 2021

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

de novo, absent from gnomAD, already known pathogenic. -

Generalized epilepsy with febrile seizures plus, type 1 Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	.;.;.;H;.;.;H;.;.;.
PhyloP100		3.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.3	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0	.;.;.;D;D;.;D;D;D;.
Vest4		0.98, 0.97, 0.97, 0.97
MutPred		0.88		.;Loss of MoRF binding (P = 0.032);.;Loss of MoRF binding (P = 0.032);.;.;Loss of MoRF binding (P = 0.032);.;.;.;
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs121918784; hg19: chr2-166895947; COSMIC: COSV57681333; COSMIC: COSV57681333;