rs121917993

Positions:

chr2-165994212-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001165963.4(SCN1A):c.4786C>T(p.Arg1596Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,456 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1596L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:2

Conservation

PhyloP100: 7.88

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:

LOC102724058 (HGNC:):

LOC102724058 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a repeat IV (size 298) in uniprot entity SCN1A_HUMAN there are 62 pathogenic changes around while only 3 benign (95%) 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 chrnull-null-null-null is described in UniProt as null.

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, 0.958

PP5

Variant 2-165994212-G-A is Pathogenic according to our data. Variant chr2-165994212-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165994212-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4 link	c.4786C>T	p.Arg1596Cys	missense_variant	28/29	ENST00000674923.1	NP_001159435.1	P35498-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN1A	ENST00000674923.1 link	c.4786C>T	p.Arg1596Cys	missense_variant	28/29		NM_001165963.4	ENSP00000501589.1	P35498-1
SCN1A	ENST00000303395.9 link	c.4786C>T	p.Arg1596Cys	missense_variant	27/28	5		ENSP00000303540.4	P35498-1
SCN1A	ENST00000375405.7 link	c.4753C>T	p.Arg1585Cys	missense_variant	25/26	5		ENSP00000364554.3	P35498-2
SCN1A	ENST00000409050.1 link	c.4702C>T	p.Arg1568Cys	missense_variant	25/26	5		ENSP00000386312.1	P35498-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460456

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726552

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000235

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2022	Published functional studies demonstrate loss of function (Kluckova et al., 2020); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the intracellular loop between S2 and S3 of the fourth homologous domain; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18930999, 28202706, 29144225, 27781031, 31009440, 23527921, 17903680, 17347258, 24328833, 32238909, 32538476, 26188943, 32090326, 32086284, 27465585, 34226156, 21248271, 33841294, 32581296) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 28, 2020	- -

Generalized epilepsy with febrile seizures plus, type 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 31, 2022	_x000D_ Criteria applied: PS4, PM1, PM5, PM2_SUP, PP2, PP3 -
Likely pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Dec 11, 2019	ACMG evidence PS2, PP2, PP3 -

Severe myoclonic epilepsy in infancy

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 26, 2020	This variant was identified as de novo (maternity and paternity confirmed). -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -

Autosomal dominant epilepsy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 30, 2022

Variant summary: SCN1A c.4786C>T (p.Arg1596Cys) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250168 control chromosomes. c.4786C>T has been reported in the literature in multiple individuals affected with SCN1A-Related Seizure Disorder (example, Depienne_2008, Harkin_2007, Claes_2009, Diugos_2007, Kim_2014). These data indicate that the variant is very likely to be associated with disease. Multiple 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/likely 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

Oct 28, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1596 of the SCN1A protein (p.Arg1596Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe epilepsy (PMID: 17347258, 17903680, 26188943, 27781031). 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: 68553). 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%. This variant disrupts the p.Arg1596 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21248271, 26188943). 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. -

Focal epilepsy

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.96

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

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

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.9

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

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.97, 0.97, 0.96

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

5.9

Varity_R

0.73

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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