2-166048928-C-G

Variant names:

• chr2-166048928-C-G
• rs779184118
• NM_001165963.4:c.986G>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.986G>C​(p.Gly329Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G329C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.12
• Publications: 3 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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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 chr2-166048929-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 206933.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, 0.888
• PP5: Variant 2-166048928-C-G is Pathogenic according to our data. Variant chr2-166048928-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1032678.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.986G>C	p.Gly329Ala	missense_variant	Exon 10 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.986G>C	p.Gly329Ala	missense_variant	Exon 10 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.986G>C	p.Gly329Ala	missense_variant	Exon 9 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.986G>C	p.Gly329Ala	missense_variant	Exon 7 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.986G>C	p.Gly329Ala	missense_variant	Exon 9 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 329 of the SCN1A protein (p.Gly329Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with genetic epilepsy with febrile seizures plus (PMID: 28084635). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1032678). 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.Gly329 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32538476; 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

Jul 11, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the first 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; This variant is associated with the following publications: (PMID: 28084635, 36939041) -

Severe myoclonic epilepsy in infancy Pathogenic:1

Oct 19, 2018

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 28084635] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;.;D;.;.;D;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;.;.;M;M;.;M;M;M;M
PhyloP100		4.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.0	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.023	.;.;.;D;.;.;D;.;D;T
Polyphen		1.0, 0.74	.;.;.;D;P;.;D;P;P;.
Vest4		0.77, 0.89, 0.86, 0.79
MutPred		0.64		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.97
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.75
gMVP		0.94
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: rs779184118; hg19: chr2-166905438;