rs794726754

Variant names:

• chr2-165992261-TAAAC-T
• rs794726754
• NM_001165963.4:c.5010_5013delGTTT

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.5010_5013delGTTT​(p.Phe1671ThrfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN1A NM_001165963.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.16

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 49 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165992261-TAAAC-T is Pathogenic according to our data. Variant chr2-165992261-TAAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 189914.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.5010_5013delGTTT	p.Phe1671ThrfsTer8	frameshift_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.5010_5013delGTTT	p.Phe1671ThrfsTer8	frameshift_variant	Exon 29 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.5010_5013delGTTT	p.Phe1671ThrfsTer8	frameshift_variant	Exon 28 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4977_4980delGTTT	p.Phe1660ThrfsTer8	frameshift_variant	Exon 26 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4926_4929delGTTT	p.Phe1643ThrfsTer8	frameshift_variant	Exon 26 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Aug 11, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.5010_5013delGTTT: p.Phe1671ThrfsX8 (F1671TfsX8) in exon 26 of the SCN1A gene (NM_001165963.1). The normal sequence with the bases that are deleted in braces is: CGTT{GTTT}AACA. The c.5010_5013delGTTT mutation in the SCN1A gene has been reported previously as a de novo mutation in association with SCN1A-related disorders (Claes et al., 2001; Depienne et al., 2009). The deletion causes a frameshift starting with codon Phenylalanine 1671, changes this amino acid to a Threonine residue and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Phe1671ThrfsX8. This mutation is predicted to cause loss of normal protein function through protein truncation as the last 339 amino acids of the SCN1A protein are replaced with 7 incorrect amino acids. The variant is found in EPILEPSY panel(s). -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN1A: PS2:Very Strong, PM2 -

Severe myoclonic epilepsy in infancy Pathogenic:2

Nov 19, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP -

Dec 20, 2014

Center for Bioinformatics, Peking University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Aug 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with Dravet syndrome and early infantile epileptic encephalopathy (PMID: 11359211, 26993267). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SCN1A protein in which other variant(s) (p.Lys1846Serfs*11, p.Arg1886*) have been determined to be pathogenic (PMID: 11359211, 14504318, 17054684, 18930999, 21719429). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 189914). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe1671Thrfs*8) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 339 amino acid(s) of the SCN1A protein. -

Epileptic encephalopathy Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Developmental and epileptic encephalopathy 6B Pathogenic:1

Sep 04, 2023

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. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000189914 /PMID: 11359211). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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: rs794726754; hg19: chr2-166848771;