rs863223345

Variant names:

• chr12-51789350-G-A
• rs863223345
• NM_001330260.2:c.4351G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001330260.2(SCN8A):​c.4351G>A​(p.Gly1451Ser) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:2
• Conservation: PhyloP100: 10.0

Genes affected

SCN8A (HGNC:10596): (sodium voltage-gated channel alpha subunit 8) This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN8A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 0.78755 (below the threshold of 3.09). Trascript score misZ: 10.436 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonus, familial, 2, infantile convulsions and choreoathetosis, cognitive impairment with or without cerebellar ataxia, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 13, benign familial infantile epilepsy, seizures, benign familial infantile, 5.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 12-51789350-G-A is Pathogenic according to our data. Variant chr12-51789350-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51789350-G-A is described in Lovd as [Pathogenic]. Variant chr12-51789350-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4351G>A	p.Gly1451Ser	missense_variant	Exon 24 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4351G>A	p.Gly1451Ser	missense_variant	Exon 24 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4228G>A	p.Gly1410Ser	missense_variant	Exon 23 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.4228G>A	p.Gly1410Ser	missense_variant	Exon 23 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4351G>A	p.Gly1451Ser	missense_variant	Exon 24 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4351G>A	p.Gly1451Ser	missense_variant	Exon 24 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4384G>A	p.Gly1462Ser	missense_variant	Exon 23 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4228G>A	p.Gly1410Ser	missense_variant	Exon 22 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 13 Pathogenic:3 Other:1

May 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been previously reported as de novo in a similarly affected individual (PMID: 25725044). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:25725044). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96>=0.6, 3CNET: 0.973>=0.75). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 13. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN8A c.4351G>A (p.Gly1451Ser) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249572 control chromosomes. c.4351G>A has been reported in the literature as a recurrent de-novo variant in individuals affected with features of SCN8A-related Epileptic Encephalopathy 13 (example, PMID: 25725044, 31026061, 29100083, 27165006). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an apparent loss of channel activity in HEK cell assay in-vitro (PMID: 25725044). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=4; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Dec 19, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (gnomad.broadinstitute.org) This variant has been seen in at least one individual with cerebelar ataxia. It was reported in de novo cases with features associated with developmental and epileptic encephalopathy. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 25725044) -

Apr 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, showing a 10-fold decrease in current density compared to wildtype, consistent with a loss of function (PMID: 25725044); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S6 of the third homologous domain; This variant is associated with the following publications: (PMID: 25725044, 32090326, 35325842, 27165006, 33915942, 31887642, 30615093, 32916281, 32845893, 29100083, 34979445, 38113761, 26029160, 38250573, 31026061, 35627257, 26900580) -

Inborn genetic diseases Pathogenic:1

Feb 16, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4351G>A (p.G1451S) alteration is located in exon 24 (coding exon 23) of the SCN8A gene. This alteration results from a G to A substitution at nucleotide position 4351, causing the glycine (G) at amino acid position 1451 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD), the SCN8A c.4351G>A alteration was not observed, with coverage at this position. This alteration has been reported de novo in multiple unrelated patients with epileptic encephalopathy (Blanchard, 2015; Hamdan, 2017; Denis, 2019). The p.G1451 amino acid is conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional analysis demonstrated that the p.G1451S alteration showed decreased current densities (Blanchard, 2015). Using whole-cell patch clamp measurements in HEK293 cells transfected with wildtype or mutated SCN8A cDNA encoding the NaV1.6α subunit, cells expressing wildtype channels exhibited substantial voltage-evoked currents, while current densities in cells expressing the G1451S mutant were about 10-fold smaller than wildtype-transfected cells which was comparable to those in non-transfected cells. The p.G1451S alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1451 of the SCN8A protein (p.Gly1451Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 25725044, 29100083, 31026061). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 192318). 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 SCN8A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN8A function (PMID: 25725044). For these reasons, this variant has been classified as Pathogenic. -

Complex neurodevelopmental disorder Other:1

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Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.3	D;D;D;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.019	D;D;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.74
MutPred		0.73		Loss of catalytic residue at L1456 (P = 0.1723);.;.;.;Loss of catalytic residue at L1456 (P = 0.1723);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.86
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs863223345; hg19: chr12-52183134;