chr2-165991549-G-A

Variant names:

• chr2-165991549-G-A
• rs121918793
• NM_001165963.4:c.5726C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.5726C>T​(p.Thr1909Ile) variant causes a missense 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 10.0
• Publications: 10 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 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 2-165991549-G-A is Pathogenic according to our data. Variant chr2-165991549-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68669.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.5726C>T	p.Thr1909Ile	missense_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.5726C>T	p.Thr1909Ile	missense_variant	Exon 29 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.5726C>T	p.Thr1909Ile	missense_variant	Exon 28 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.5693C>T	p.Thr1898Ile	missense_variant	Exon 26 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.5642C>T	p.Thr1881Ile	missense_variant	Exon 28 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant that is likely pathogenic has been identified in the SCN1A gene. The T1909I variant has been previously reported as T1899I (using alternative nomenclature) in an individual with severe myoclonic epilepsy of infancy; parental testing was not reported (Ohmori et al., 2002). Functional studies have demonstrated that T1909I results in a abnormal channel function (Ohmori et al., 2006). The T1909I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1909I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a conserved position predicted to be within the C-terminal cytoplasmic domain. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Severe myoclonic epilepsy in infancy Pathogenic:1 Other:1

Jan 06, 2017

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability; severe and pharmacoresistant epilepsy (starting with febrile convulsions); pyramidal syndrome; tremor and myoclonus; dysmorphism; scoliosis -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Developmental and epileptic encephalopathy Pathogenic:1

Feb 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1909 of the SCN1A protein (p.Thr1909Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and Dravet syndrome (PMID: 12083760, 15277629, 18076640, 28708303). In at least one individual the variant was observed to be de novo. This variant is also known as c.5696C>T (p.Thr1899Ile). ClinVar contains an entry for this variant (Variation ID: 68669). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN1A function (PMID: 17054685). This variant disrupts the p.Thr1909 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21248271, 28102150). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;.;.;D;.;D;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;.;.;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;.;.;H;.;H;.;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	.;.;.;D;.;D;.;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;.;.;D;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;D;.;D;D
Polyphen		1.0	.;.;.;.;D;.;D;D;.
Vest4		0.83, 0.89, 0.86, 0.86
MutPred		0.39		.;.;.;Loss of loop (P = 0.0112);.;Loss of loop (P = 0.0112);.;.;.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.79
gMVP		0.82
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918793; hg19: chr2-166848059;