rs796053004

Positions:

• chr2-166009736-G-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.3985C>T​(p.Arg1329Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.22

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-166009736-G-A is Pathogenic according to our data. Variant chr2-166009736-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 206816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166009736-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.3985C>T	p.Arg1329Ter	stop_gained	23/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1	n.176-5877G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3985C>T	p.Arg1329Ter	stop_gained	23/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.193-5877G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 04, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2023	Reported previously as a maternally inherited variant in siblings with Dravet syndrome; their mother was mosaic for the variant with a history of migraines (Selmer et al., 2009); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22719002, 24836964, 21248271, 21269283, 18413471, 19400878, 22409937, 16430863, 15880351, 15508915, 25754450, 22151702, 31164858, 31864146, 32090326, 35074891, 35813073, 18930999, 19673951) -

Severe myoclonic epilepsy in infancy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 17, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2022

The c.3985C>T (p.R1329*) alteration, located in coding exon 20 of the SCN1A gene, consists of a C to T substitution at nucleotide position 3985. This changes the amino acid from a Arginine (R) to a stop codon at amino acid position 1329. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although loss of function alterations in SCN1A have been associated with Dravet syndrome, haploinsufficiency for SCN1A has not been established as a mechanism of disease for SCN1A-related developmental and epileptic encephalopathy, SCN1A-related hemiplegic migraine, and SCN1A-related GEFS+. Based on the available evidence, the SCN1A c.3985C>T (p.R1329*) alteration is classified as pathogenic for Dravet syndrome; however, its clinical significance for SCN1A-related developmental and epileptic encephalopathy, SCN1A-related hemiplegic migraine, and SCN1A-related GEFS+ is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with Dravet syndrome (Demos, 2019; Depienne, 2009; Gertler, 2020; Selmer, 2009; Zuberi, 2011). Based on the available evidence, this alteration is classified as pathogenic. -

Developmental and epileptic encephalopathy, 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 16, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, 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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variant comparable to the one identified in this case have very strong previous evidence for pathogenicity. NMD-predicted variants are well-reported as pathogenic in ClinVar and the literature (PMID: 18930999). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. It has also been reported in the literature de novo in an individual with Dravet syndrome (PMID: 18930999). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 07, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 206816). This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 18930999, 25754450). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1329*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). -

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

Pathogenic, no assertion criteria provided

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Feb 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.99, 0.99, 0.99, 0.99
GERP RS		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs796053004; hg19: chr2-166866246; COSMIC: COSV57681669;