rs121917980

Variant names:

• chr2-165991928-C-T
• rs121917980
• NM_001165963.4:c.5347G>A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.5347G>A​(p.Ala1783Thr) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1783V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.85

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 19 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S6 of repeat IV (size 22) in uniprot entity SCN1A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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 chr2-165991927-G-A is described in Lovd as [Pathogenic].
• 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, 0.952
• PP5: Variant 2-165991928-C-T is Pathogenic according to our data. Variant chr2-165991928-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68570.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.5347G>A	p.Ala1783Thr	missense_variant	Exon 29 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.5347G>A	p.Ala1783Thr	missense_variant	Exon 29 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.5347G>A	p.Ala1783Thr	missense_variant	Exon 28 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.5314G>A	p.Ala1772Thr	missense_variant	Exon 26 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.5263G>A	p.Ala1755Thr	missense_variant	Exon 26 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:3 Other:1

Dec 20, 2014

Center for Bioinformatics, Peking University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 31, 2018

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala1783Thr (GCG>ACG): c.5347 G>A in exon 26 of the SCN1A gene (NM_001165963.1). A heterozygous missense variant was identified in a patient with Dravet syndrome. It involves a change of Guanine for Adenine at position 5347 of the coding DNA, which is located in exon 26 of the gene and generates a change from Alanine to Threonine (p .Ala1783Thr) at the protein level. This variant was described in 2007 by Harkin et al (Brain. 2007 Mar; 130 (Pt 3): 843-5) associated with Dravet syndrome and it is reported as pathogenic in the following databases: i) HGMD, ii) Ensembl, iii) ClinVar. According to the ACMG criteria, the variant was classified as pathogenic (PS2, PS3, PM1, PM2, PP2, PP3, PP4, PP5). The variant was confirmed by capillary sequencing (Sanger) in the index case. Sanger sequencing searching for this variant was performed on both parents giving a negative result, so it is presumed to be a de novo variant. -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068570). A different missense change at the same codon (p.Ala1783Val) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068571). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Aug 17, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala1783Thr (GCG>ACG): c.5347 G>A in exon 26 of the SCN1A gene (NM_001165963.1) The A1783T missense mutation in the SCN1A gene has been reported previously as a de novo mutation in association with Dravet syndrome and other SCN1A-related disorders (for examples, see Harkin et al., 2007; Sun et al., 2010; Heron et al., 2010). This mutation alters a highly conserved position predicted to be within the transmembrane segment S6 of the fourth homologous domain of the SCN1A protein, and another missense mutation at the same codon (A1783V) has also been published in association with SCN1A-related disorders in an external mutation database. The A1783T substitution is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The variant is found in EPILEPSY,CHILD-EPI panel(s). -

May 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1783 of the SCN1A protein (p.Ala1783Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant severe myoclonic epilepsy of infancy and Dravet syndrome (PMID: 17347258, 30321769). In at least one individual the variant was observed to be de novo. This variant is also known as 5314G>A (Ala1772Thr). ClinVar contains an entry for this variant (Variation ID: 68570). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3;C5543353:Developmental and epileptic encephalopathy 6B Pathogenic:1

Jul 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized epilepsy with febrile seizures plus, type 2 Pathogenic:1

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5347G>A;p.(Ala1783Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 68570; PMID: 30321769; PMID: 26096185; PMID: 17347258; PMID: 22071555; PMID: 19589774) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ion_trans;PKD_channel) - PM1. This variant is not present in population databases (rs121917980- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 68571) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 17347258) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 26096185) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Developmental and epileptic encephalopathy 6B Pathogenic:1

Jan 28, 2022

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;D;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;.;.;.;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	.;.;.;H;.;H;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	.;.;.;D;.;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;.;D;.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;.;.;D;.;D;.;D;D
Polyphen		1.0	.;.;.;.;D;.;D;D;.
Vest4		0.94, 0.95, 0.95, 0.94
MutPred		0.75		.;.;.;Gain of glycosylation at A1783 (P = 0.0513);.;Gain of glycosylation at A1783 (P = 0.0513);.;.;.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.70
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: rs121917980; hg19: chr2-166848438;