rs121917975

Variant names:

• chr2-165994365-T-C
• rs121917975
• NM_001165963.4:c.4633A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.4633A>G​(p.Ile1545Val) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1545T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.93
• Publications: 7 publications found

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S1 of repeat IV (size 17) in uniprot entity SCN1A_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-165994364-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2847117.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-165994365-T-C is Pathogenic according to our data. Variant chr2-165994365-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 68551.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.4633A>G	p.Ile1545Val	missense_variant	Exon 28 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4633A>G	p.Ile1545Val	missense_variant	Exon 28 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4633A>G	p.Ile1545Val	missense_variant	Exon 27 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4600A>G	p.Ile1534Val	missense_variant	Exon 25 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.4549A>G	p.Ile1517Val	missense_variant	Exon 27 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy Pathogenic:1 Other:1

Mar 13, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Ile1545Val variant in SCN1A was identified by our study in one individual with Duane retraction syndrome, epilepsy, developmental delay, hypotonia, joint hypermobility, and craniofacial dysmorphisms, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio genome analysis showed this variant to be de novo. We believe this is a possible phenotype expansion for SCN1A-related epilepsy. The p.Ile1545Val variant in SCN1A has been previously reported in at least 6 individuals with SCN1A-related epilepsy (PMID: 30619928, PMID: 28202706, PMID: 17347258, PMID: 32371413, PMID: 31440721, ClinVar Accession SCV001423679.1). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 4 individuals with confirmed paternity and maternity (PMID: 30619928, PMID: 17347258, PMID: 32371413, ClinVar Accession SCV001423679.1). The p.Ile1545Val variant is located in a region of SCN1A that is essential to ion transport, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 21248271). This variant was absent from large population studies. The number of missense variants reported in SCN1A in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. This variant has also been reported in ClinVar (Variation ID: 68551) and has been interpreted as pathogenic by Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital and Invitae. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant SCN1A-related epilepsy. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4_Moderate, PM1_Supporting, PM2_Supporting, PP2 (Richards 2015). -

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Developmental and epileptic encephalopathy Pathogenic:1

Mar 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1545 of the SCN1A protein (p.Ile1545Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SCN1A-related conditions (PMID: 17347258, 28202706, 30619928). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68551). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Nov 30, 2018

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

[ACMG/AMP: PS2, PM1, PM2, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. -

not provided Pathogenic:1

Sep 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the transmembrane segment S1 of the fourth homologous domain; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22409937, 17347258, 35074891, 39033378, 31440721, 30619928, 28202706, 32371413) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;.;.;D;.;.;D;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D;.;D;.;.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.5	.;.;.;L;.;.;L;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.71	.;.;.;N;.;.;N;.;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.16	.;.;.;T;.;.;T;.;T;T
Sift4G	Benign	0.23	.;.;.;T;.;.;T;.;T;T
Polyphen		0.60	.;.;.;.;P;.;.;P;P;.
Vest4		0.82, 0.87, 0.84, 0.84
MutPred		0.46		.;.;.;Gain of helix (P = 0.0696);.;.;Gain of helix (P = 0.0696);.;.;.;
MVP		0.94
MPC		1.5
ClinPred		0.94	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.83
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: 1

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

Other links and lift over

dbSNP: rs121917975; hg19: chr2-166850875;