2-166038098-G-A

Position:

• chr2-166038098-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.2624C>T​(p.Thr875Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T875K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a helix (size 11) in uniprot entity SCN1A_HUMAN there are 4 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 chr2-166038098-G-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN1A. . Gene score misZ 5.2206 (greater than the threshold 3.09). Trascript score misZ 7.6022 (greater than threshold 3.09). GenCC has associacion of gene with migraine, familial hemiplegic, 3, familial hemiplegic migraine, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, myoclonic-astatic epilepsy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 6, familial or sporadic hemiplegic migraine, arthrogryposis, Lennox-Gastaut syndrome, generalized epilepsy with febrile seizures plus, type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 2-166038098-G-A is Pathogenic according to our data. Variant chr2-166038098-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166038098-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.2624C>T	p.Thr875Met	missense_variant	18/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2624C>T	p.Thr875Met	missense_variant	18/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2624C>T	p.Thr875Met	missense_variant	17/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2591C>T	p.Thr864Met	missense_variant	15/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.2540C>T	p.Thr847Met	missense_variant	15/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460730 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	The variant has been observed in at least two similarly affected unrelated individuals (PMID: 10742094, 23195492) and has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 10742094, 23195492). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12086636, 11567038, 14702334). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.983>=0.6, 3CNET: 0.989>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:18930999). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2024	Reported previously in association with GEFS+ and severe myoclonic epilepsy of infancy, borderline phenotype (PMID: 23195492, 10742094, 18804930); Published functional studies demonstrate a damaging effect and show that this variant impairs the channel function by enhancing channel inactivation (PMID: 11422459, 11567038, 12086636); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the intracellular loop between with S4 and S5 transmembrane segments of the second homologous domain; This variant is associated with the following publications: (PMID: 14672992, 11422459, 14702334, 11567038, 12086636, 23195492, 16550559, 18804930, 20831750, 31440721, 35074891, 28717674, 10742094, 36672771) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -

Severe myoclonic epilepsy in infancy Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 20, 2017	This variant was identified as de novo (maternity and paternity confirmed). -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2016

The p.T875M variant (also known as c.2624C>T), located in coding exon 15 of the SCN1A gene, results from a C to T substitution at nucleotide position 2624. The threonine at codon 875 is replaced by methionine, an amino acid with similar properties. This variant was originally identified in eleven affected members of a family with generalized epilepsy with febrile seizures plus type 2 (Escayg A et al. Nat. Genet., 2000 Apr;24:343-5). This alteration was also reported in a patient with severe myoclonic epilepsy borderline (Wang JW et al. Epilepsy Res., 2012 Dec;102:195-200). This variant was previously reported in the SNPDatabase as rs121918623, but not in NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 875 of the SCN1A protein (p.Thr875Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with generalized epilepsy with febrile seizures plus in a family (GEFS+) and borderline severe myoclonic epilepsy in infancy (SMEB) (PMID: 10742094, 23195492; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12883). 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: 11567038, 12086636, 14702334). This variant disrupts the p.Thr875 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18930999, 20522430, 28192756). 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. -

SCN1A-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2024

The SCN1A c.2624C>T variant is predicted to result in the amino acid substitution p.Thr875Met. This variant was reported in multiple individuals with generalized epilepsy with febrile seizures plus (see for example, Escayg et al. 2000. PubMed ID: 10742094). It has been reported to be de novo and segregate with disease (Table S1, Halfmeyer et al. 2022. PubMed ID: 36672771; Escayg et al. 2000. PubMed ID: 10742094). Functional studies indicate this variant affects protein function (Spampanato et al. 2004. PubMed ID: 14702334). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

May 14, 2024

- -

Generalized epilepsy with febrile seizures plus, type 1 Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;.;.;H;.;.;H;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.7	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0	.;.;.;D;D;.;D;D;D;.
Vest4		0.87, 0.81, 0.81, 0.82
MutPred		0.78		.;Gain of MoRF binding (P = 0.13);.;Gain of MoRF binding (P = 0.13);.;.;Gain of MoRF binding (P = 0.13);.;.;.;
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.84
gMVP		0.98

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: rs121918623; hg19: chr2-166894608; COSMIC: COSV57669847; COSMIC: COSV57669847;