Submissions for variant NM_001148.6(ANK2):c.10858T>A (p.Trp3620Arg)

gnomAD frequency: 0.00001  dbSNP: rs199473346

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779424	SCV000916040	likely pathogenic	Cardiac arrhythmia, ankyrin-B-related	2017-05-03	criteria provided, single submitter	clinical testing	The ANK2 c.10858T>A (p.Trp3620Arg) missense variant, frequently referred to as c.4603 T>A (p.Trp1535Arg), is reported in three studies and has been identified in a heterozygous state at least seven individuals of Japanese ancestry with cardiac arrhythmias. This includes five individuals with long QT syndrome (LQTS), one individual with Brugada syndrome, and one individual with ventricular arrhythmia. The p.Trp1535Arg variant is also reported in one individual with suspected LQTS, an asymptomatic child with borderline QT prolongation and a family history of sudden cardiac death. Segregation information is not available for these individuals (Zhou et al. 2006; Ichikawa et al. 2016; Nishiyama et al. 2017). The p.Trp3620Arg variant was absent from 150 Japanese controls and is reported at a frequency of 0.00046 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Trp3620Arg variant is classified aslikely pathogenic for ANK2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000794010	SCV000933392	uncertain significance	Long QT syndrome	2018-09-13	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in several individuals affected with long QT syndrome or Brugada syndrome (PMID: 16864073, 27784853). This variant is also known as c.4603T>A p.W1535R in the literature. ClinVar contains an entry for this variant (Variation ID: 67596). This variant is present in population databases (rs199473346, ExAC 0.05%). This sequence change replaces tryptophan with arginine at codon 3620 of the ANK2 protein (p.Trp3620Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058341	SCV000089861	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16864073). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.