rs575368466

Variant names:

• chr2-165994211-C-T
• rs575368466
• NM_001165963.4:c.4787G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001165963.4(SCN1A):​c.4787G>A​(p.Arg1596His) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1596C) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 6.09
• Publications: 11 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)

LOC102724058 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr2-165994212-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68553.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, 0.913
• PP5: Variant 2-165994211-C-T is Pathogenic according to our data. Variant chr2-165994211-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448255.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4787G>A	p.Arg1596His	missense_variant	Exon 28 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4787G>A	p.Arg1596His	missense_variant	Exon 28 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4787G>A	p.Arg1596His	missense_variant	Exon 27 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4754G>A	p.Arg1585His	missense_variant	Exon 25 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.4703G>A	p.Arg1568His	missense_variant	Exon 27 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151852 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250118 AF XY: 0.00000740

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74272

African (AFR) AF: 0.0000241 AC: 1 AN: 41502

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This substitution is predicted to be in the intracellular loop between the S2 and S3 transmembrane segments of the fourth homologous domain; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21248271, 28150151, 31009440, 34055682, 35571373, 32090326, 26188943) -

Feb 04, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Mar 20, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4787G>A (p.R1596H) alteration is located in exon 25 (coding exon 25) of the SCN1A gene. This alteration results from a G to A substitution at nucleotide position 4787, causing the arginine (R) at amino acid position 1596 to be replaced by a histidine (H). Based on the available evidence, the SCN1A c.4787G>A (p.R1596H) alteration is classified as pathogenic for SCN1A-related seizure disorders; however, its clinical significance for SCN1A-related hemiplegic migraine is uncertain. Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/250118) total alleles studied. The highest observed frequency was 0.006% (1/16216) of African alleles. This variant was identified in one or more individuals with features consistent with SCN1A-related seizure disorders and segregated with disease in at least one family (Hoffman-Zacharska, 2015; Stawicka, 2024; Fang, 2022; Zuberi, 2011; Brunklaus, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Developmental and epileptic encephalopathy Pathogenic:1

Apr 24, 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 1596 of the SCN1A protein (p.Arg1596His). This variant is present in population databases (rs575368466, gnomAD 0.007%). This missense change has been observed in individual(s) with early onset epileptic encephalopathy and/or febrile seizures (PMID: 21248271, 26188943). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 448255). 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: 18804930, 18930999, 24328833, 25348405, 28202706). 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. -

Severe myoclonic epilepsy in infancy Pathogenic:1

Apr 05, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;.;.;M;.;.;M;.;.;.
PhyloP100		6.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.3	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.032	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0	.;.;.;.;D;.;.;D;D;.
Vest4		0.95, 0.93, 0.93, 0.94
MutPred		0.63		.;.;.;Loss of catalytic residue at R1596 (P = 0.0296);.;.;Loss of catalytic residue at R1596 (P = 0.0296);.;.;.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.63
gMVP		0.98
Mutation Taster		=0/100	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: rs575368466; hg19: chr2-166850721;