rs587780446

Positions:

• chr2-165991477-CG-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

This summary comes from the ClinGen Evidence Repository: The c.5797del variant in SCN1A is a single nucleotide deletion predicted to cause a frameshift at amino acid position 1933 leading to a premature stop codon (p.Arg1933Glufs*3). The variant is located within the last exon and thus predicted to escape nonsense mediated decay. The truncated region is not known to be important for protein function, as missense variants reported in the region do not meet PLP per these criteria. Furthermore, LOF variants within this exon are relatively common in gnomAD v4.1. As such, this variant does not meet criteria to apply PVS1. This variant has been identified in a family in which 2 affected siblings with developmental and epileptic encephalopathy (DEE) harbored the variant, in addition to an unaffected parent and 2 unaffected siblings (LabCorp Genetics, Inc. internal data). Given the severity of the phenotype and presence in multiple unaffected family members, this case was not included as evidence for PS4. The variant is absent from the population database, gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for autosomal dominant SCN1A-related disorder, based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM2_Supporting. (version 1.0, approved September 24, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA269784/MONDO:0018214/067

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 1.78

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.5797del	p.Arg1933GlufsTer3	frameshift_variant	29/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1	n.176-24135del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.5797del	p.Arg1933GlufsTer3	frameshift_variant	29/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.193-24135del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 28, 2013

- -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 23, 2017

In summary, this is a rare frameshift variant with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Experimental studies have not been reported for this truncating variant and it is currently unknown if the last 77 amino acids of the SCN1A protein are critical for its function. This variant is not present in population databases (rs587780446, ExAC no frequency) and has not been reported in the literature in individuals with an SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 130208). This sequence change deletes 1 nucleotide from exon 26 of the SCN1A mRNA (c.5797delC), causing a frameshift at codon 1933. This creates a premature translational stop signal in the last exon of the SCN1A mRNA (p.Arg1933Glufs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt 4 and delete the last 73 amino acids of the SCN1A protein. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2017

The c.5797delC variant in the SCN1A gene has not been published previously as a pathogenic variant nor as a benign variant, to our knowledge. It is reported in ClinVar with conflicting classifications (variant of uncertain significance and pathogenic variant) by other clinical laboratories (SCV000152597.1 and SCV000548753.1; Landrum et al., 2016). This variant causes a frameshift in the C-terminus of the protein, starting with codon Arginine 1933, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Arg1933GlufsX3. It is predicted to result in protein truncation, as the last 77 amino acids are lost and replaced with 2 incorrect amino acids. The c.5797delC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

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: rs587780446; hg19: chr2-166847987;