2-166009753-G-T

Variant names:

• chr2-166009753-G-T
• rs1057521746
• NM_001165963.4:c.3968C>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.3968C>A​(p.Pro1323His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar 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: 9.80

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

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a helix (size 10) in uniprot entity SCN1A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• 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 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, 0.947
• PP5: Variant 2-166009753-G-T is Pathogenic according to our data. Variant chr2-166009753-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 383819.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.3968C>A	p.Pro1323His	missense_variant	Exon 23 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3968C>A	p.Pro1323His	missense_variant	Exon 23 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.3968C>A	p.Pro1323His	missense_variant	Exon 22 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.3935C>A	p.Pro1312His	missense_variant	Exon 20 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.3884C>A	p.Pro1295His	missense_variant	Exon 20 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Apr 28, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P1323H variant (also known as c.3968C>A), located in coding exon 20 of the SCN1A gene, results from a C to A substitution at nucleotide position 3968. The proline at codon 1323 is replaced by histidine, an amino acid with similar properties. In one case study, this variant was confirmed to be de novo in a 2-year-old with suspected Dravet syndrome, whose history included a hemiconvulsive febrile seizure at 6 months of age, generalized afebrile seizures at 9 months, and an occipital seizure (induced by intermittent photo stimulation) at 11 months (Specchio N et al. Seizure, 2014 Apr;23:309-13). This variant is located in the S4 transmembrane region and is predicted to be structurally deleterious (Wu J et al. Science, 2015 Dec;350). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Feb 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro1323 (also known as p.Pro1312) amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 21868258, 31009440), which suggests that this may be a clinically significant amino acid residue. 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: 383819). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 24472396). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 1323 of the SCN1A protein (p.Pro1323His). -

not provided Pathogenic:1

Feb 25, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A published P1323H variant that is likely pathogenic has been identified in the SCN1A gene. TheP1323H variant has been reported previously as a de novo variant in an individual with Dravetsyndrome (Specchio et al., 2014). It was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. The P1323H variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a conserved position predicted to bewithin the voltage-sensor transmembrane segment S4 of the third homologous domain of the SCN1Aprotein. Different missense variants at the same position (P1323R, P1323S) as well as multiplemissense variants in nearby residues have been reported in association with SCN1A-related disorders(Stenson et al., 2014; SCN1A Variant Database), supporting the functional importance of this regionof the protein. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. Therefore, this variant is likely pathogenic; however, the possibility that it isbenign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	5.2	.;.;.;H;.;.;H;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.1	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.0050	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 1.0	.;.;.;D;D;.;D;D;D;.
Vest4		0.90, 0.91, 0.93, 0.94
MutPred		0.64		.;Loss of methylation at R1322 (P = 0.0778);.;Loss of methylation at R1322 (P = 0.0778);.;.;Loss of methylation at R1322 (P = 0.0778);.;.;.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.98

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: rs1057521746; hg19: chr2-166866263; COSMIC: COSV57679338;