chr2-166002699-C-A

Position:

• chr2-166002699-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001165963.4(SCN1A):​c.4057G>T​(p.Val1353Phe) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.90

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 11 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S5 of repeat III (size 19) in uniprot entity SCN1A_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• 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 2-166002699-C-A is Pathogenic according to our data. Variant chr2-166002699-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 577950.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4057G>T	p.Val1353Phe	missense_variant	24/29	ENST00000674923.1	NP_001159435.1
LOC102724058	NR_110598.1	n.176-12914C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4057G>T	p.Val1353Phe	missense_variant	24/29		NM_001165963.4	ENSP00000501589	P4
SCN1A-AS1	ENST00000651574.1	n.193-12914C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 09, 2018

This sequence change replaces valine with phenylalanine at codon 1353 of the SCN1A protein (p.Val1353Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant identified in the SCN1A gene is located in the transmembrane spanning D3-S5 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. For these reasons, this variant has been classified as Pathogenic. The observation of one or more missense substitutions at this codon (p.Val1353Leu) in affected individuals suggests that this may be a clinically significant residue (PMID: 11254444, 14672992). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in an individual affected with SCN1A-related disease (Invitae). This variant is not present in population databases (ExAC no frequency). -

SCN1A-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2024

The SCN1A c.4057G>T variant is predicted to result in the amino acid substitution p.Val1353Phe. This variant has been reported in an individual with epilepsy, but no additional evidence was provided to support pathogenicity (Truty et al. 2019. PubMed ID: 31440721). This variant is absent from the gnomAD general population database, indicating it is rare. An alternate nucleotide change affecting the same amino acid (c.4057G>C; p.Val1353Leu) has been reported in individuals with generalized epilepsy (Wallace et al. 2001. PubMed ID: 11254444), and functional studies support its pathogenicity (Berecki et al. 2019. PubMed ID: 30779207; Lossin et al. 2003. PubMed ID: 14672992). The c.4057G>T (p.Val1353Phe) variant is documented in ClinVar as pathogenic by one laboratory (https://www.ncbi.nlm.nih.gov/clinvar/variation/577950/), and it has been detected de novo in affected individuals in clinical testing (ClinVar, PreventionGenetics internal data). Taken together, the c.4057G>T (p.Val1353Phe) variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;.;M;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;.;.;D;.;D;D
Polyphen		1.0, 0.99	.;.;D;D;.;D;D;D;.
Vest4		0.93, 0.93, 0.92, 0.89
MutPred		0.75		.;.;Loss of catalytic residue at V1353 (P = 0.0372);.;.;Loss of catalytic residue at V1353 (P = 0.0372);.;.;.;
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -29

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

Publications

LitVar

Other links and lift over

dbSNP: rs121917954; hg19: chr2-166859209;