rs121918624

Positions:

• chr2-166052882-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.664C>T​(p.Arg222Ter) variant causes a stop gained change involving the alteration of a 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 8.00

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)

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 2-166052882-G-A is Pathogenic according to our data. Variant chr2-166052882-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166052882-G-A is described in Lovd as [Pathogenic]. Variant chr2-166052882-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.664C>T	p.Arg222Ter	stop_gained	8/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.664C>T	p.Arg222Ter	stop_gained	8/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+16752G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:7

Pathogenic, criteria provided, single submitter	research	Center for Bioinformatics, Peking University	Dec 20, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012889, PMID:11359211). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26096185, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Dec 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The stop gained c.664C>T (p.Arg222Ter) variant in the SCN1A gene has been observed in individual(s) with SCN1A-related conditions (Claes, L et al.,2001). This variant is absent in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic/ Pathoegnic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.664C>T in SCN1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2016	Variant summary: The SCN1A c.664C>T (p.Arg222X) variant results in a premature termination codon, predicted to cause a truncated or absent SCN1A protein, which is a commonly known mechanism for disease. The variant is absent in 116,872 control chromosomes and has been reported by multiple reputable clinical labs as pathogenic. The literature reports this variant in numerous SMEI patients, many of whom have confirmed de novo inheritance. Functional study proved that variant did not generate Na+current and showed significantly slower kinetics of recovery from inactivation compared to WT (Bechi_2012). Taken together, this variant has been classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Jan 01, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2022	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; Published functional studies demonstrate an inability to generate sodium current and slower kinetics of recovery from inactivation (Bechi et al., 2012); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26096185, 14738421, 30321769, 22409937, 23195492, 25525159, 28837158, 22150645, 11359211, 19522081, 24168886, 29100083, 31780880, 31864146, 32090326, 29573403, 33278787) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 03, 2016	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2016

The p.R222* pathogenic mutation (also known as c.664C>T), located in coding exon 5 of the SCN1A gene, results from a C to T substitution at nucleotide position 664. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been reported in an individual with severe myoclonic epilepsy of infancy (Claes L et al. Am. J. Hum. Genet., 2001 Jun;68:1327-32). 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 13, 2023

This sequence change creates a premature translational stop signal (p.Arg222*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SCN1A-related conditions (PMID: 11359211, 23195492, 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12889). For these reasons, this variant has been classified as Pathogenic. -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 30, 2023

Criteria applied: PVS1,PS2,PS4,PS3_SUP,PM2_SUP -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.95, 0.95, 0.95, 0.95
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs121918624; hg19: chr2-166909392; COSMIC: COSV100321806;