chr12-51807101-G-A

Position:

• chr12-51807101-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PP3_Moderate PM6 PM2_Supporting PM5_Strong PS3 PS4

This summary comes from the ClinGen Evidence Repository: The c.5615G>A variant in SCN8A is a missense variant predicted to cause a subtitution of arginine by glutamine at amino acid 1872 (p.Arg1872Gln). This variant has been reported as de novo in at least 3 individuals with unconfirmed parental relationships (PMIDs: 2664715, 28333917, 28387369) (PM6) and at least an additional 8 individuals without informative segregation data available (PMIDs: 25568300, 29655203, 29930392, 32509551, 34395220, 30968951) (PS4). Multiple other amino acid substitutions at the same amino acid position have been previously reported and meet pathogenic per these criteria (p.Arg1872Gly, p.Arg1872Trp, p.Arg1872Leu) (PM5). Heterologous expression with voltage clamping assay has shown significant hyperpolarizing shift in voltage dependence of activation and significant depolarizing shift of voltage dependence of fast inactivation (PS3). The variant is rare (1 allele) in the population database, gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM6, PM5, PS3, PM2_Supporting (version 1.0; approved 5/23/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586302/MONDO:0100038/070

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:2
• Conservation: PhyloP100: 8.15

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 17 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.5615G>A	p.Arg1872Gln	missense_variant	27/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.5615G>A	p.Arg1872Gln	missense_variant	27/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.5492G>A	p.Arg1831Gln	missense_variant	26/26		NP_001171455.1
SCN8A	NM_001369788.1	c.5492G>A	p.Arg1831Gln	missense_variant	26/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.5615G>A	p.Arg1872Gln	missense_variant	27/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.5615G>A	p.Arg1872Gln	missense_variant	27/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.5648G>A	p.Arg1883Gln	missense_variant	26/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.5492G>A	p.Arg1831Gln	missense_variant	25/25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249080 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461706 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	May 28, 2021	- -

Complex neurodevelopmental disorder Pathogenic:1 Other:1

Pathogenic, reviewed by expert panel	curation	ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen	May 09, 2024	The c.5615G>A variant in SCN8A is a missense variant predicted to cause a subtitution of arginine by glutamine at amino acid 1872 (p.Arg1872Gln). This variant has been reported as de novo in at least 3 individuals with unconfirmed parental relationships (PMIDs: 2664715, 28333917, 28387369) (PM6) and at least an additional 8 individuals without informative segregation data available (PMIDs: 25568300, 29655203, 29930392, 32509551, 34395220, 30968951) (PS4). Multiple other amino acid substitutions at the same amino acid position have been previously reported and meet pathogenic per these criteria (p.Arg1872Gly, p.Arg1872Trp, p.Arg1872Leu) (PM5). Heterologous expression with voltage clamping assay has shown significant hyperpolarizing shift in voltage dependence of activation and significant depolarizing shift of voltage dependence of fast inactivation (PS3). The variant is rare (1 allele) in the population database, gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM6, PM5, PS3, PM2_Supporting (version 1.0; approved 5/23/23). -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -

Cognitive impairment with or without cerebellar ataxia;C3281191:Developmental and epileptic encephalopathy, 13;C4310728:Seizures, benign familial infantile, 5;C5193056:Myoclonus, familial, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 20, 2024

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1872 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24888894, 25951352, 26029160, 26900580, 27779742). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SCN8A function (PMID: 26900580). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 253297). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 25568300, 26647175, 26900580, 28387369). In at least one individual the variant was observed to be de novo. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1872 of the SCN8A protein (p.Arg1872Gln). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2020

Published functional studies demonstrate hyperactivity of the sodium channel by impairing channel inactivation (Wagnon et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This substitution is predicted to be within the C-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 26029160, 24194747, 25568300, 26647175, 26900580, 28387369, 29574705, 29100083, 28333917, 30968951, 30185235, 31077350, 30552426, 32090326, 32509551) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;.;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.1	D;D;.;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;.;.;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.70
MutPred		0.40		Gain of disorder (P = 0.1343);.;.;.;Gain of disorder (P = 0.1343);
MVP		0.98
MPC		2.4
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.67
gMVP		0.91

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: rs796053229; hg19: chr12-52200885;