chr2-165991735-AGTTT-A

Position:

• chr2-165991735-AGTTT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.5536_5539del​(p.Lys1846SerfsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 6.18

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 56 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165991735-AGTTT-A is Pathogenic according to our data. Variant chr2-165991735-AGTTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 189881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.5536_5539del	p.Lys1846SerfsTer11	frameshift_variant	29/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-23872_176-23869del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.5536_5539del	p.Lys1846SerfsTer11	frameshift_variant	29/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-23872_193-23869del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN1A-related epilepsy (PMID: 28488083). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple premature termination variants downstream have been reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has previously been described as pathogenic in multiple patients, including as de novo in patients with Dravet syndrome or infantile onset generalised tonic-clonic seizures (ClinVar, VCGS, PMIDs: 21719429, 29141279, 18413471). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2019	Frameshift variant in the C-terminus predicted to result in protein truncation as the last 164 amino acids are lost and replaced with 10 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18930999, 31864146, 26096185, 32090326, 16458823, 17347258, 18413471, 11359211, 17054684, 14504318, 21719429, 30945278, 31765958, 31031587) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	SCN1A: PS2, PS4, PM2, PVS1:Moderate -

Severe myoclonic epilepsy in infancy Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A heterozygous one-base pair deletion in exon 29 of the SCN1A gene (c.5536_5539delAAAC) that results in a frameshift and premature truncation of the protein 11 amino acids downstream to codon 1846(p.K1846SfsTer11) was detected. This frameshift variant is not reported in both the 1000 genomes and gnomAD databases. This variant is predicted to be damaging by Mutation taster and the region is conserved across species. There are 14 downstream pathogenic loss of function variants, with the furthest variant being 80 residues downstream of this variant. This indicates that the region is critical to protein function. This gene has a low rate of benign loss of function variants as indicated by a low upper bound of the observed/expected confidence interval 0.07. The observed variant is a loss of function variant in this gene, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_001159435.1:p.M1I and 448 others. The observed variant has been previously classified as Pathogenic in ClinVar (Variation ID 189881 as of 2021-03-04) with respect to severe myoclonic epilepsy in infancy and 2 other conditions with a status of (2 stars) criteria provided, multiple submitters, no conflicts. Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines. -

SCN1A Seizure Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 19, 2023

The SCN1A c.5536_5539del (p.Lys1846SerfsTer11) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. This variant has been reported in individuals with a phenotype consistent with SCN1A seizure disorders, the majority of which were found in a de novo state (PMID: 11359211; 18413471; 20431604; 21719429; 34055682; 34145886; 35701389; 35886038). The p.Lys1846SerfsTer11 variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The variant was identified in a de novo state. Based on the available evidence, the c.5536_5539del (p.Lys1846SerfsTer11) variant is classified as pathogenic for SCN1A seizure disorders. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2017

The c.5536_5539delAAAC pathogenic mutation, located in coding exon 26 of the SCN1A gene, results from a deletion of 4 nucleotides at nucleotide positions 5536 to 5539, causing a translational frameshift with a predicted alternate stop codon (p.K1846Sfs*11). This mutation has been detected in several individuals with Dravet syndrome, severe myoclonic epilepsy of infancy, and/or epileptic encephalopathy (Claes L et al. Am. J. Hum. Genet., 2001 Jun;68:1327-32; Heron SE et al. J. Med. Genet., 2010 Feb;47:137-41; Claes LR et al. Hum. Mutat., 2009 Oct;30:E904-20); Sun H et al. J. Hum. Genet., 2010 Jul;55:421-7; Spatola M et al. Eur. Neurol., 2013 Nov;69:119-21; Catarino CB et al. Brain, 2011 Oct;134:2982-3010; Wallace RH et al. Neurology, 2003 Sep;61:765-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

This sequence change creates a premature translational stop signal (p.Lys1846Serfs*11) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 164 amino acid(s) of the SCN1A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (also known as severe myoclonic epilepsy of infancy) (PMID: 11359211, 14504318, 21719429). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189881). For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy 6B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Heidelberg University

Jun 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs794726726; hg19: chr2-166848245;