12-51789350-G-A

Position:

• chr12-51789350-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The ENST00000354534.11(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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1451G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A ENST00000354534.11 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000354534.11
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN8A. . Gene score misZ 0.78755 (greater than the threshold 3.09). Trascript score misZ 10.278 (greater than threshold 3.09). GenCC has associacion of gene with 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192318.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Uncertain_significance=1, not_provided=2}. 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/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4351G>A	p.Gly1451Ser	missense_variant	24/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4351G>A	p.Gly1451Ser	missense_variant	24/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4228G>A	p.Gly1410Ser	missense_variant	23/26		NP_001171455.1
SCN8A	NM_001369788.1	c.4228G>A	p.Gly1410Ser	missense_variant	23/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4351G>A	p.Gly1451Ser	missense_variant	24/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.4351G>A	p.Gly1451Ser	missense_variant	24/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2023	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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 01, 2020

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect SCN8A protein function (PMID: 25725044). This variant has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 31026061, 25725044, 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 192318). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 1451 of the SCN8A protein (p.Gly1451Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 02, 2024

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) -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Athena Diagnostics

Dec 20, 2016

- -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

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
MutationTaster	Benign	1.0	D;D
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;