Brugada syndrome and cardiac sodium channel disease

Gene: KCNH2

Comment on list classification: Demoting from Amber to Red inline with the review by Matthew Edwards, due to limited evidence and disputed classification for Brugada syndrome by ClinGen (assessed on 06/10/2025 - https://search.clinicalgenome.org/CCID:008947)

Created: 5 Mar 2026, 5:02 p.m. | Last Modified: 5 Mar 2026, 5:02 p.m.

Panel Version: 3.15

Red List (low evidence)

Gene now disputed by ClinGen expert panel: previously reported variants have little evidence for causation, and some patch-clamp studies against pathogenicity (PMIDs: 16043162, 18692916, 38648771). Mouse and cell culture rescue models do not recapitulate BrS phenotype, no valid functional evidence exists. [No variants (beyond 'cold' VUS) detected in gene in our BrS lab cohort , ~600 probands]

Created: 27 Feb 2026, 11:24 a.m. | Last Modified: 27 Feb 2026, 11:24 a.m.

Panel Version: 3.14

Publications

• PMID: 39895654

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

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

• 24400717
• 23874304
• 16043162

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

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.

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

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

• PMID: 16043162
• 19174314
• 18692916

Mode of pathogenicity
Other

Comment when marking as ready: Not on Manchester diagnostic panel

Created: 11 Feb 2016, 12:20 p.m.

I don't know