Brugada syndrome and cardiac sodium channel disease
Gene: KCNH2Comment on phenotypes: KCNH2 is also associated with Long QT syndrome 2, OMIM:613688 and Short QT syndrome 1, OMIM:609620Created: 2 Mar 2021, 10:20 a.m. | Last Modified: 2 Mar 2021, 10:20 a.m.
Panel Version: 2.7
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
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/16043162Created: 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
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.
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/10154Created: 20 Feb 2019, 2:47 p.m.
Mode of inheritance
Disputed
Phenotypes
Brugada syndrome; MONDO_0015263
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
Comment when marking as ready: Not on Manchester diagnostic panelCreated: 11 Feb 2016, 12:20 p.m.
Phenotypes for gene: KCNH2 were changed from Brugada/Brugada like syndrome to Brugada syndrome, MONDO:0015263
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
Gene: kcnh2 has been classified as Amber List (Moderate Evidence).
Gene: kcnh2 has been classified as Green List (High Evidence).
Tag missense tag was added to gene: KCNH2.
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
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
Publications for gene: KCNH2 were set to
Mode of inheritance for gene: KCNH2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
This gene has been classified as Red List (Low Evidence).
KCNH2 was added to Brugada syndromepanel. Sources: Expert list