rs1057518801

Positions:

• chr2-165130238-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PS3 PS2 PM6 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2624T>C variant in SCN3A is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 875 (p.Ile875Thr). The variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) with DEE (PMIDs: 29740860, 29466837) (PS2_Very Strong) and as a de novo occurrance with unconfirmed parental relationship in a least 2 individuals with DEE (PMIDs: 29286531, 28191890) (PM6_Moderate), with additional case evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). Studies have observed that when expressed in mammalian cells in culture, this variant causes a gain-of-function effect on the mutant channels as evidenced by a significant leftward/hyperpolarized shift in the voltage dependence of activation, an increase in the persistent/inactivating current, and a rightward/depolarizing shift in the voltage of inactivation (PS3; PMID:29466837). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant developmental and epilepstic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2_VS, PM6_Moderate, PM2_Supporting, PS3. (Version 1; July 7, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16043377/MONDO:0100062/069

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 O:2
• Conservation: PhyloP100: 7.47

Genes affected

SCN3A (HGNC:10590): (sodium voltage-gated channel alpha subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN3A	NM_006922.4	c.2624T>C	p.Ile875Thr	missense_variant	17/28	ENST00000283254.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN3A	ENST00000283254.12	c.2624T>C	p.Ile875Thr	missense_variant	17/28	1	NM_006922.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Developmental and epileptic encephalopathy, 62 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss of function effects have been shown to be associated with focal epilepsy whilst gain of function effects have been shown to be associated with epileptic encephalopathy (PMID: 29466837, 28235671). (N) 0200 - Variant is predicted to result in a missense amino acid change from an isoleucine to a threonine (exon 17). (N) 0251 - Variant is heterozygous. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0301 - Variant is absent from gnomAD. (P) 0600 - Variant is located in an annotated domain or motif (S4-S5 linker of ion transport domain II (PMID: 30146301, 29466837)). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported de novo in patients with epileptic encephalopathy with cerebral cortical development malformations (ClinVar; Decipher; PMID: 29740860, 30146301, 29466837, 30904718). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Cell lines expressing this variant demonstrated gain of function effects (PMID: 30146301, 29466837). (P) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 17, 2020	- -
Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Dec 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Jul 20, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2022	This missense change has been observed in individual(s) with polymicrogyria and early infantile epileptic encephalopathy (PMID: 29466837, 29740860; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 875 of the SCN3A protein (p.Ile875Thr). ClinVar contains an entry for this variant (Variation ID: 373960). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN3A function (PMID: 29466837). 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 SCN3A protein function. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2015	The I875T variant in the SCN3A gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The I875T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I875T 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 occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The I875T variant is a strong candidate for a disease-causing variant, however, the possibility it may be a rare benign variant cannot be excluded. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Epilepsy, familial focal, with variable foci 4 Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. This variant arose de novo in at least one reported proband. -
not provided, no classification provided	literature only	GeneReviews	-	Most common recurrent pathogenic variant; associated with treatment-resistant seizures, severe/profound developmental delay/intellectual disability, and malformation of cortical development (pachy- or polymicrogyria) -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 29, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:2 Other:1

Pathogenic, reviewed by expert panel	curation	ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen	May 09, 2024	The c.2624T>C variant in SCN3A is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 875 (p.Ile875Thr). The variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) with DEE (PMIDs: 29740860, 29466837) (PS2_Very Strong) and as a de novo occurrance with unconfirmed parental relationship in a least 2 individuals with DEE (PMIDs: 29286531, 28191890) (PM6_Moderate), with additional case evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). Studies have observed that when expressed in mammalian cells in culture, this variant causes a gain-of-function effect on the mutant channels as evidenced by a significant leftward/hyperpolarized shift in the voltage dependence of activation, an increase in the persistent/inactivating current, and a rightward/depolarizing shift in the voltage of inactivation (PS3; PMID: 29466837). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant developmental and epilepstic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2_VS, PM6_Moderate, PM2_Supporting, PS3. (Version 1; July 7, 2023). -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Jul 05, 2023	- -

Polymicrogyria;C0424605:Developmental delay Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.8	D;D;.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;.;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.87
MutPred		0.91		Loss of stability (P = 0.0229);Loss of stability (P = 0.0229);.;.;.;
MVP		0.98
MPC		3.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.97

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: rs1057518801; hg19: chr2-165986748; COSMIC: COSV51817927;