Submission Details

ANK2 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). ANK2, which encodes the ankyrin B protein, has been implicated in a number of arrhythmia phenotypes but has been classified as Disputed for both Brugada syndrome and Long QT syndrome by the respective Gene Curation Expert Panels. Variants in ANK2 have been detected in 3 patients/families with CPVT-like symptoms (Mohler et al, 2004, PMID:15178757; Mohler et al, 2007, PMID:17242276). However the population frequencies of these variants are too high to be an autosomal dominant cause of CPVT – p.Leu1622Ile (gnomAD max MAF = 0.034), p.Arg1788Trp (gnomAD max MAF = 0.002) and p.Val1516Asp (gnomAD max MAF = 0.004). AnkB heterozygous null mice have been shown to display exercise and epinephrine-induced polymorphic ventricular arrhythmias before death (Mohler et al, 2003, PMID:12571597). While this phenotype can be rescued with transfection of wild type ankyrin-B, mutant ankyrin-B with the human arrhythmia-associated variants described above (and variants associated with other arrhythmias) were unable to rescue this phenotype (Mohler et al, 2004, PMID:15178757; Mohler et al, 2007, PMID:17242276). Nevertheless, despite this experimental evidence, there is no convincing human genetic evidence to associate ANK2 as an autosomal dominant cause of CPVT and therefore this gene has been classified as Disputed. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).