Brugada syndrome

Gene: KCNH2

Amber List (moderate evidence)

KCNH2 (potassium voltage-gated channel subfamily H member 2)
EnsemblGeneIds (GRCh38): ENSG00000055118
EnsemblGeneIds (GRCh37): ENSG00000055118
OMIM: 152427, Gene2Phenotype
KCNH2 is in 3 panels

8 reviews

Ivone Leong (Genomics England Curator)

Comment on phenotypes: KCNH2 is also associated with Long QT syndrome 2, OMIM:613688 and Short QT syndrome 1, OMIM:609620
Created: 2 Mar 2021, 10:20 a.m. | Last Modified: 2 Mar 2021, 10:20 a.m.
Panel Version: 2.7

James Eden (Manchester)

Red List (low evidence)

Gene not currently tested on Manchester panel. Table 1 of Nielsen 2013 presents genetic contribution to Brugada syndrome. No particularly strong evidence for KCNH2 over other non-SCN5A causes of Brugada syndrome.
Created: 25 Sep 2019, 12:59 p.m. | Last Modified: 25 Sep 2019, 12:59 p.m.
Panel Version: 1.43

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

Phenotypes
Long QT syndrome 2 613688; Short QT syndrome 1 609620

Publications

Rebecca Whittington (South West GLH)

Red List (low evidence)

Long QT syndrome 2 (OMIM 613688), Short QT syndrome 1 (OMIM 609620), {Long QT syndrome 2, acquired, susceptibility to} (OMIM 613688)
Created: 25 Mar 2019, 4:30 p.m.
Overwhelming evidence for LQT. No strong evidence for Brugada. PMID:25626866. https://www.ncbi.nlm.nih.gov/pubmed/24400717. https://www.ncbi.nlm.nih.gov/pubmed/16043162
Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

Louise Daugherty (Genomics England Curator)

Comment on list classification: After clinical review it was felt there was enough evidence to promote to green. The external reviewer outlines 3 cases with a Brugada / mixed Brugada and SQTS phenotype with missense variants in this gene which meets our threshold.. It is possible there is a gain of function mechanism here. Further cases will help to define the mutational spectrum and the predominant phenotype e.g. SQTS / Brugada.
Created: 1 Mar 2019, 5:27 p.m.

Ellen McDonagh (Genomics England Curator)

Red List (low evidence)

Comment on list classification: Demoted from Green to Amber due to additional expert review from the South West GLH and ClinGen group conclusion that there is not enough evidence for this to be involved in Brugada syndrome. Final decision to be made by the NHSE GMS specialist group.
Created: 25 Mar 2019, 5:18 p.m.
This gene was given a validity classification of Disputed by the ClinGen validity curation group and is reflected by providing a Red review here.The gene-disease summary was downloaded on 20th Feb 2019.For the full report and publications see the ClinGen Gene Validity Curation for each gene here: https://search.clinicalgenome.org/kb/gene-validity/10154
Created: 20 Feb 2019, 2:47 p.m.

Mode of inheritance
Disputed

Phenotypes
Brugada syndrome; MONDO_0015263

Jules Hancox (University of Bristol)

Green List (high evidence)

Two HERG (KCNH2) sequence variations, G873S and N985S, were reported in two SCN5A mutation-negative patients with ECG features typical of BrS. The in vitro characterization suggested an augmentation of early current and simulations suggested a loss-of-dome of right ventricular APs (Verkerk et al, 2005; PMID: 16043162).

A subsequent patient study identified a hERG mutation (R1135H) in a short QT syndrome case with a mixed BrS SQTS phenotype. In vitro work showed a slowing of hERG deactivation. In silico work suggested that this could cause increased hERG current early during repolarization and under some conditions loss-of-dome in right ventricular AP simulations (refs: PMID 19174314 PMID: 18692916)
Created: 15 Nov 2018, 7:57 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Brugada syndrome; long QT syndrome; short QT syndrome

Publications

Mode of pathogenicity
Other

Caroline Wright (Genomics England Curator)

Comment when marking as ready: Not on Manchester diagnostic panel
Created: 11 Feb 2016, 12:20 p.m.

Oxford Medical Genetics Laboratory (OUH NHS Foundation Trust)

I don't know

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • South West GLH
  • Expert list
Phenotypes
  • Brugada syndrome, MONDO:0015263
Tags
missense
OMIM
152427
Clinvar variants
Variants in KCNH2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

2 Mar 2021, Gel status: 2

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: KCNH2 were changed from Brugada/Brugada like syndrome to Brugada syndrome, MONDO:0015263

2 Mar 2021, Gel status: 2

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: KCNH2 were changed from Brugada/Brugada like syndrome; Long QT syndrome 2 613688; Short QT syndrome 1 609620 to Brugada/Brugada like syndrome

25 Mar 2019, Gel status: 2

Entity classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

Gene: kcnh2 has been classified as Amber List (Moderate Evidence).

1 Mar 2019, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: kcnh2 has been classified as Green List (High Evidence).

1 Mar 2019, Gel status: 1

Added Tag

Louise Daugherty (Genomics England Curator)

Tag missense tag was added to gene: KCNH2.

21 Feb 2019, Gel status: 1

Added New Source, Set mode of inheritance

Ellen McDonagh (Genomics England Curator)

Source South West GLH was added to KCNH2. Mode of inheritance for gene KCNH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

12 Dec 2018, Gel status: 1

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: KCNH2 were changed from Brugada/Brugada like syndrome to Brugada/Brugada like syndrome; Long QT syndrome 2 613688; Short QT syndrome 1 609620

12 Dec 2018, Gel status: 1

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: KCNH2 were set to

12 Dec 2018, Gel status: 1

Set mode of inheritance

Sarah Leigh (Genomics England Curator)

Mode of inheritance for gene: KCNH2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

11 Feb 2016, Gel status: 1

Gene classified by Genomics England curator

Caroline Wright (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

13 Jul 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

KCNH2 was added to Brugada syndromepanel. Sources: Expert list