rs587777721

Variant names:

• chr12-51806336-G-A
• rs587777721
• NM_001330260.2:c.4850G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51806336-G-A
• chr12-51806336-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_001330260.2(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. R1617P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A NM_001330260.2 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 transmembrane_region Helical; Name=S4 of repeat IV (size 16) in uniprot entity SCN8A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001330260.2
• 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-C is described in Lovd as [Likely_pathogenic].
• 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, 0.954
• 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 rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4850G>A	p.Arg1617Gln	missense_variant	Exon 27 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4850G>A	p.Arg1617Gln	missense_variant	Exon 27 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4727G>A	p.Arg1576Gln	missense_variant	Exon 26 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.4727G>A	p.Arg1576Gln	missense_variant	Exon 26 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4850G>A	p.Arg1617Gln	missense_variant	Exon 27 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4850G>A	p.Arg1617Gln	missense_variant	Exon 27 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4883G>A	p.Arg1628Gln	missense_variant	Exon 26 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4727G>A	p.Arg1576Gln	missense_variant	Exon 25 of 25	1		ENSP00000347255.4

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

Jul 14, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Jan 04, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 24, 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 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

Oct 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 25, 2017

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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	0.97
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
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;