Long QT syndrome

Gene: ANK2

I don't know

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.

Created: 18 Nov 2019, 2:09 p.m. | Last Modified: 18 Nov 2019, 2:09 p.m.

Panel Version: 1.44

I don't know

Gene currently tested on Manchester cardiac gene panel. Only class 1-3 variants detected to date. 75 variants listed on HGMD (accessed 29/01/2019). ClinGen Knowledge Base: currently no stated association with LQT, disputed association with Brugada syndrome 1 (accessed 29/01/2019).

Created: 19 Sep 2019, 9:50 a.m. | Last Modified: 19 Sep 2019, 9:50 a.m.

Panel Version: 1.38

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

Phenotypes
Long QT syndrome 4 (600919); Cardiac arrhythmia, ankyrin-B-related (600919)

Publications

• 12571597

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

I don't know

Cardiac arrhythmia, ankyrin-B-related (OMIM 600919), Long QT syndrome 4 (OMIM 600919)

Created: 25 Mar 2019, 4:30 p.m.

Does not look like classic LQT, patients that have variants sometime asymptomatic. Some variants reported are too frequent.PMID:26132555. PMID: 16253912. PMID: 17242276. PMID:15178757.

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

Green List (high evidence)

Gene on Royal Brompton diagnostic panel. Only VUS reported from our lab. Limited evidence for association with arrhythmia phenotypes rather than classic LQTS, and likely only rare LOF causative. But gene should possibly exist on this panel as well as larger arrhythmia panel due to possible clinical overlap/differential diagnosis?

Created: 19 Mar 2019, 3:54 p.m. | Last Modified: 28 Nov 2019, 10:54 a.m.

Panel Version: 1.45

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

Publications

• 12571597

Green List (high evidence)

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

Comment when marking as ready: On Manchester long QT diagnostic panel

Created: 7 Mar 2016, 4:14 p.m.

Comment on list classification: Current diagnostic

Created: 7 Mar 2016, 4:12 p.m.

I don't know

Comment on list classification: Due to the presence of lots of VUS variants in this gene for Long QT syndrome, the decision was made to demote this gene from Green to Red in the NHSE GMS Cardiology Specialist Group meeting call on 25th January 2019, but it should be added to/kept on the larger arrhythmia panels as Green.

Created: 4 Mar 2019, 9:10 p.m.

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

On the Inherited Cardiac Condition Genes panel reported in: Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes, Pua et al, Journal of Cardiovascular Translational Research, online Feb 2016 (doi:10.​1007/​s12265-016-9673-5). The panel contains disease-causing, putatively pathogenic, research and phenocopy genes, and it is unclear from the publication whether this gene falls into the disease-causing category. No. of mutations indicated in supplemental table = 10.

Created: 19 Feb 2016, 10:39 a.m.

Publications

• doi:10.​1007/​s12265-016-9673-5
• 12571597

Comment on list classification: From OMIM: Mohler et al. (2004; 15178757) described 5 ANK2 mutations where prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes

Created: 29 Jan 2016, 1:37 p.m.

Green List (high evidence)

Ankyrin-B syndrome which is caused by pathogenic mutations in the ANK2 gene is a clinical entity distinct from classical Long QT syndrome. Mohler et al 2004 and Mohler et al 2007 identified that individuals with ANK2 mutations had a range of arrhythmic phenotypes - a prolonged QT interval was not always a feature. Caution should be applied when investigating variants detected in this gene as many variants that have previously been reported as pathogenic have been detected at high frequencies in ExAC. However there is good evidence that variants in this gene cause life threatening arrhythmias. Would like to see this gene on a general arrhythmia panel if not also on the LQTS panel.

Created: 25 Jan 2019, 12:41 p.m.

Ankyrin-B syndrome, which is caused by pathogenic mutations in the ANK2 gene, is a clinical entity distinct from classical Long QT syndrome. Mohler et al 2004 and Mohler et al 2007 identified that individuals with ANK2 mutations had a range of arrhythmic phenotypes; a prolonged QT interval was not always a feature.
Caution should be applied when investigating variants detected in this gene as many variants that have previously been reported as ‘pathogenic’ have been detected at high frequencies in ExAC.

Created: 2 Mar 2016, 4:09 p.m.

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