2-166037930-C-T

Position:

• chr2-166037930-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3_Moderate PM6_Strong PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The c.2792G>A variant in SCN1A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 931 (p.Arg931His). The variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 2 individual(s) with Dravet syndrome (PMIDs: 28079314, 35072530) (PM6_Strong), and in at least 3 unrelated individuals with Dravet syndrome with unknown inheritance (PMIDs: 21719429, 31031587, 33067208) (PS4), with additional evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.966, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant Dravet syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM6_Strong, PS4, PM2_Supporting, PP3_Moderate. (version 1; approved August 4, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA303154/MONDO:0100135/067

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• 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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.2792G>A	p.Arg931His	missense_variant	18/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2792G>A	p.Arg931His	missense_variant	18/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2792G>A	p.Arg931His	missense_variant	17/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2759G>A	p.Arg920His	missense_variant	15/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.2708G>A	p.Arg903His	missense_variant	15/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen	May 09, 2024	The c.2792G>A variant in SCN1A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 931 (p.Arg931His). The variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 2 individual(s) with Dravet syndrome (PMIDs: 28079314, 35072530) (PM6_Strong), and in at least 3 unrelated individuals with Dravet syndrome with unknown inheritance (PMIDs: 21719429, 31031587, 33067208) (PS4), with additional evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.966, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant Dravet syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM6_Strong, PS4, PM2_Supporting, PP3_Moderate. (version 1; approved August 4, 2023). -
Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 15, 2015	- -

Migraine, familial hemiplegic, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center of Excellence for Medical Genomics, Chulalongkorn University

Sep 08, 2002

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

This missense change has been observed in individual(s) with Dravet syndrome (PMID: 22780858, 25243660, 27231140, 28079314). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg931 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12083760, 18076640). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 189869). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 931 of the SCN1A protein (p.Arg931His). -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 12, 2023

This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the second homologous domain; 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; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 33067208, 21719429, 21248271, 32613771, 31031587, 35074891, 26096185, 22780858, 30868114, 35944423, 35072530, 28079314, 31440721) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;.;.;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.8	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.042	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 0.42	.;.;.;D;B;.;D;B;B;.
Vest4		0.81, 0.91, 0.91, 0.94
MutPred		0.62		.;Loss of catalytic residue at R931 (P = 0.0581);.;Loss of catalytic residue at R931 (P = 0.0581);.;.;Loss of catalytic residue at R931 (P = 0.0581);.;.;.;
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.85
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

Other links and lift over

dbSNP: rs794726718; hg19: chr2-166894440;