chr2-166037931-G-A

Variant names:

• chr2-166037931-G-A
• rs121918788
• NM_001165963.4:c.2791C>T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.2791C>T​(p.Arg931Cys) 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. 12/21 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. R931H) has been classified 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:6 O:1
• Conservation: PhyloP100: 8.05

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 17 ACMG points.

• PM1: In a repeat II (size 272) in uniprot entity SCN1A_HUMAN there are 49 pathogenic changes around while only 2 benign (96%) 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 chr2-166037930-C-T is described in Lovd as [Likely_pathogenic].
• 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 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, 0.938
• PP5: Variant 2-166037931-G-A is Pathogenic according to our data. Variant chr2-166037931-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166037931-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.2791C>T	p.Arg931Cys	missense_variant	Exon 18 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.2791C>T	p.Arg931Cys	missense_variant	Exon 18 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.2791C>T	p.Arg931Cys	missense_variant	Exon 17 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.2758C>T	p.Arg920Cys	missense_variant	Exon 15 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.2707C>T	p.Arg903Cys	missense_variant	Exon 15 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Feb 01, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg931Cys missense variant in the SCN1A gene has been reported as a de novo variant in multiple patients with Dravet syndrome and other SCN1A-related disorders (Ohmori et al., 2002; Depienne et al., 2009; an external mutation database). This amino acid substitution is non-conservative, as a positively charged Arginine residue is replaced by an uncharged Cysteine residue, and the gain of a Cysteine could affect disulfide bond formation in the protein. Arg931Cys alters a highly conserved position in the pore loop between the S5 and S6 segments of the second transmembrane domain, and many other variants have been reported in this region of the protein. -

Apr 30, 2014

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe myoclonic epilepsy in infancy Pathogenic:1 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 25, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Aug 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 931 of the SCN1A protein (p.Arg931Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 12083760, 18076640). In at least one individual the variant was observed to be de novo. This variant is also known as Arg921Cys. ClinVar contains an entry for this variant (Variation ID: 68598). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg931 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25243660, 27231140, 28079314). 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

Nov 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN1A c.2791C>T variant is predicted to result in the amino acid substitution p.Arg931Cys. This variant has been reported, with many de novo occurrences, in multiple individuals with SCN1A-related disorders (Ohmori et al. 2002. PubMed ID: 12083760; Truty R et al. 2019. PubMed ID: 31440721; Gertler TS et al. 2019. PubMed ID: 31864146; Gall K et al. 2021. PubMed ID: 34469436; Jiang T et al. 2021. PubMed ID: 34489640; Chen C et al. 2022. PubMed ID: 35571373; Wyers et al. 2021. PubMed ID: 3344514). Alternate nucleotide changes affecting the same amino acid (p.Arg931Ser, p.Arg931His, p.Arg931Pro) have been reported in individuals with SCN1A-related disease and reported to be pathogenic (Do TT et al. 2017. PubMed ID: 28079314). The c.2791C>T (p.Arg931Cys) variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	.;.;.;H;.;.;H;.;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-7.7	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 1.0	.;.;.;D;D;.;D;D;D;.
Vest4		0.87, 0.97, 0.97, 0.97
MutPred		0.66		.;Gain of catalytic residue at P930 (P = 0.0072);.;Gain of catalytic residue at P930 (P = 0.0072);.;.;Gain of catalytic residue at P930 (P = 0.0072);.;.;.;
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.89
gMVP		1.0

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: rs121918788; hg19: chr2-166894441; COSMIC: COSV57687876; COSMIC: COSV57687876;