rs587777721

chr12-51806336-G-Achr12-51806336-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_014191.4(SCN8A):c.4850G>A(p.Arg1617Gln) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1617L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_014191.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-51806336-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 976197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SCN8A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 12-51806336-G-A is Pathogenic according to our data. Variant chr12-51806336-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 156106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51806336-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.4850G>A	p.Arg1617Gln	missense_variant	27/27	ENST00000627620.5
SCN8A	NM_014191.4	c.4850G>A	p.Arg1617Gln	missense_variant	27/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.4727G>A	p.Arg1576Gln	missense_variant	26/26
SCN8A	NM_001369788.1	c.4727G>A	p.Arg1576Gln	missense_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.4850G>A	p.Arg1617Gln	missense_variant	27/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.4850G>A	p.Arg1617Gln	missense_variant	27/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 13 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 14, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2018

The p.R1617Q pathogenic mutation (also known as c.4850G>A), located in coding exon 26 of the SCN8A gene, results from a G to A substitution at nucleotide position 4850. The arginine at codon 1617 is replaced by glutamine, an amino acid with highly similar properties. This mutation was first identified in an individual with non-syndromic intellectual disability (Rauch A et al. Lancet, 2012 Nov;380:1674-82). It has also been reported in individuals with seizure disorders (Ohba C et al. Epilepsia, 2014 Jul;55:994-1000; Larsen J et al. Neurology, 2015 Feb;84:480-9; Kong W et al. Epilepsia, 2015 Mar;56:431-8; Dyment DA et al. Clin. Genet., 2015 Jul;88:34-40). In ND7/23 cells, this mutation causes elevated channel activity due to impaired channel inactivation (Wagnon JL et al. Ann Clin Transl Neurol, 2016 Feb;3:114-23). In addition, internal structural analysis indicates that this variant is part of a known motif needed for protein function and there are known pathogenic variants at equivalent positions in the protein (Spampanato J et al. J. Neurosci., 2004 Nov;24:10022-34; Mantegazza M et al. J. Neurosci., 2005 Mar;25:3341-9; Laezza F et al. Mol. Cell. Neurosci., 2009 Oct;42:90-101; Catterall WA. Neuron, 2010 Sep;67:915-28; Yan Z et al. Cell, 2017 Jul;170:470-482.e11). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1617 of the SCN8A protein (p.Arg1617Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathies (PMID: 23020937, 24888894, 25046240, 25568300, 25785782, 26029160, 29588952). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 156106). 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 SCN8A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN8A function (PMID: 26900580). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2021

Published functional studies demonstrate a damaging effect resulting in channel hyperactivity (Wagnon et al., 2016); 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; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 31692161, 25785782, 24194747, 26029160, 23020937, 24888894, 25568300, 25046240, 28554332, 29588952, 30171078, 28191890, 29655203, 32090326, 31175295, 33004838, 33442870, 26900580) -

developmental delay with seizures Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Aug 25, 2017

- -

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	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D;D;.;.;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.;.;.
Sift4G	Benign	0.093	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.88
MutPred		0.76		Loss of MoRF binding (P = 0.0363);.;.;.;Loss of MoRF binding (P = 0.0363);
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.84
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs587777721; hg19: chr12-52200120;