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Genetic epilepsy syndromes

Gene: SCN9A

Amber List (moderate evidence)

SCN9A (sodium voltage-gated channel alpha subunit 9)
EnsemblGeneIds (GRCh38): ENSG00000169432
EnsemblGeneIds (GRCh37): ENSG00000169432
OMIM: 603415, Gene2Phenotype
SCN9A is in 14 panels

10 reviews

Alison Callaway (Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust)

I don't know

Three more cases in the literature (including twin sisters). Two of the families had the p.(G327E) variant and the other had a frameshift. Have not assessed these variants using ACMG, but think this gene should be at least on the watchlist.
Created: 22 Nov 2019, 9:58 a.m. | Last Modified: 22 Nov 2019, 9:58 a.m.
Panel Version: 1.425

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

Rebecca Foulger (Genomics England curator)

Red List (low evidence)

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted SCN9A from Green to Amber.
Created: 25 Nov 2019, 8:41 p.m. | Last Modified: 25 Nov 2019, 8:41 p.m.
Panel Version: 1.435
Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.
Created: 7 Oct 2019, 9:47 a.m. | Last Modified: 7 Oct 2019, 9:47 a.m.
Panel Version: 1.351
Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Created: 5 Sep 2019, 2:52 p.m. | Last Modified: 5 Sep 2019, 2:52 p.m.
Panel Version: 1.262
As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Created: 15 Aug 2019, 10:08 a.m. | Last Modified: 15 Aug 2019, 10:08 a.m.
Panel Version: 1.230
Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Amber.
Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189

Tracy Lester (Genetics laboratory, Oxford UK)

I don't know

AD febrile seizures (type 7 and 3B), AD EIEE 6 (also AD primary erythermalgia, AD paraoxysmal extreme pain disorder and AR HSAN2D - all 'pain' phenotype not epilepsy). AD febrile seizures: Singh et al, 2009, large Utah family - identified a het missense variant and in 2 unrelated probands 2 diff het missense variants identified. No functional work done. AD EIEE6: Singh et al 2009, 2 patients with Dravet syndrome het mutation in SCN9A (K655R). One of these patients also had an SCN1A variant, which was also detected in a patient with AD febrile seizures. Possible that SCN9A gene is a modifier of Dravet syndrome as 9/109 patients with dravet syndrome also had an SCN9A variant including 6 patients who were double heterozygous for SCN9A and SCN1A mutations and 3 patients with only het SCN9A mutations - consistent with multifactoral inheritance.
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy, generalized, with febrile seizures plus, type 7,613863; Erythermalgia, primary,133020; Febrile seizures, familial,613863; HSAN2D,243000; Insensitivity to pain, congenital,243000; Paroxysmal extreme pain disorder,167400; Small fiber neuropathy,133020

Publications

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Associated with phenotype in OMIM and not in Gen2Phen. At least 6 variants identified in unrelated cases, 2 variants in Epilepsy, generalized, with febrile seizures plus, type 7 613863 (including affected members of a large family in Utah), 2 in unrelated cases of Febrile seizures, familial, 3B 613863 (PMID 19763161) and 2 in unrelated cases with variable epilepsy phenotypes (PMID 29500686).
Created: 4 Apr 2018, 3:29 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Amy McTague (UCL Institute of Child Health)

Red List (low evidence)

Natalie Trump (NHS - Great Ormond Street Hospital)

Red List (low evidence)

Manju Kurian (UCL-Institute of Child Health)

Red List (low evidence)

Richard Scott (North Thames GMC/UCL)

Red List (low evidence)

Ellen McDonagh (Genomics England Curator)

Added the watchlist tag.
Created: 8 Dec 2016, 10:29 a.m.

Richard Scott (Genomics England Curator)

Comment on list classification: Insufficient data to report diagnostically in a monogenic setting
Created: 8 May 2016, 7:01 p.m.

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • North West GLH
  • Wessex and West Midlands GLH
  • NHS GMS
  • NIHRBR-RD Consortium SPEED_v3.0_20170404
  • Expert
Phenotypes
  • Epilepsy, generalized, with febrile seizures plus, type 7 613863
  • Febrile seizures, familial, 3B 613863
  • {Dravet syndrome, modifier of} 607208
OMIM
603415
Clinvar variants
Variants in SCN9A
Penetrance
None
Publications
Panels with this gene

History Filter Activity

26 Nov 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: SCN9A were set to 19763161; 29500686

25 Nov 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: scn9a has been classified as Amber List (Moderate Evidence).

5 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source North West GLH was added to SCN9A.

15 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: scn9a has been classified as Green List (High Evidence).

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to SCN9A.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to SCN9A.

11 Dec 2018, Gel status: 4

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Richard Scott: Comment on list classification

26 Jun 2018, Gel status: 4

Added New Source

Sarah Leigh (Genomics England Curator)

NIHRBR-RD Consortium SPEED_v3.0_20170404 was added to SCN9A. Panel: Genetic Epilepsy Syndromes

9 Apr 2018, Gel status: 3

Set mode of inheritance

Sarah Leigh (Genomics England Curator)

Mode of inheritance for SCN9A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

4 Apr 2018, Gel status: 3

Set publications

Sarah Leigh (Genomics England Curator)

Publications for SCN9A were set to 19763161; 29500686

4 Apr 2018, Gel status: 3

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

4 Apr 2018, Gel status: 1

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for SCN9A were set to Epilepsy, generalized, with febrile seizures plus, type 7 613863; Febrile seizures, familial, 3B 613863; {Dravet syndrome, modifier of} 607208

4 Apr 2018, Gel status: 1

Set publications

Sarah Leigh (Genomics England Curator)

Publications for SCN9A were set to 19763161

4 Apr 2018, Gel status: 1

Added New Source

Sarah Leigh (Genomics England Curator)

SCN9A was added to Genetic Epilepsy Syndromes panel. Sources: Expert Review Red,Expert

4 Apr 2018, Gel status: 1

Created

Sarah Leigh (Genomics England Curator)

SCN9A was created by Sarah Leigh