rs1553545660

Positions:

• chr2-166045189-GTTTTC-G

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.1511_1515delGAAAA​(p.Arg504fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.11

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-166045189-GTTTTC-G is Pathogenic according to our data. Variant chr2-166045189-GTTTTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 461242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.1511_1515delGAAAA	p.Arg504fs	frameshift_variant	13/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.1511_1515delGAAAA	p.Arg504fs	frameshift_variant	13/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.1511_1515delGAAAA	p.Arg504fs	frameshift_variant	12/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.1511_1515delGAAAA	p.Arg504fs	frameshift_variant	10/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.1511_1515delGAAAA	p.Arg504fs	frameshift_variant	10/26	5		ENSP00000386312.1

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 06, 2017

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). This sequence change deletes 5 nucleotides from exon 10 of the SCN1A mRNA (c.1511_1515delGAAAA), causing a frameshift at codon 504. This creates a premature translational stop signal (p.Arg504Thrfs*12) and is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2019

The c.1511_1515delGAAAA pathogenic variant in the SCN1A gene has been reported previously in an individual with Dravet syndrome, however parental studies were not performed (Villeneuve et al.; 2014). The c.1511_1515delGAAAA causes a frameshift starting with codon Arginine 504, changes this amino acid to a Threonine residue and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Arg504ThrfsX12. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1511_1515delGAAAA variant is not observed in large population cohorts (Lek et al., 2016). Therefore, the presence of c.1511_1515delGAAAA is consistent with the diagnosis of an SCN1A-related disorder inthis individual. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553545660; hg19: chr2-166901699;