Submissions for variant NM_001148.6(ANK2):c.11716C>T (p.Arg3906Trp)

gnomAD frequency: 0.00094  dbSNP: rs121912706

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV001841250	SCV000050754	likely benign	Cardiac arrhythmia	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000474063	SCV000223217	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082560	SCV000557197	likely benign	Long QT syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620379	SCV000737448	benign	Cardiovascular phenotype	2022-03-16	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852983	SCV000995732	likely benign	Cardiomyopathy	2017-03-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000474063	SCV001154266	benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	ANK2: BS1, BS2
Illumina Laboratory Services, Illumina	RCV001145853	SCV001306553	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211890	SCV001363525	benign	not specified	2019-04-08	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.11716C>T (p.Arg3906Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 276816 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 270 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome (LQTS) phenotype (6.7e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Mohler et al (2004) originally reported the variant in one LQTS proband from one family without segregation analysis performed, and also, the proband of another family with unknown/uncertain LQTS phenotype and her father who was asymptomatic. This study predates the emergence of large control population datasets. Subsequently, c.11716C>T has been reported in the literature in individuals affected with LQTS and hypertrophic cardiomyopathy and also, in a stillbirth case (Sahlin_2019, Lopes_2015, Sherman_2015, Lieve_2013, Ng_2013). A co-occurrence with a pathogenic variant causative of LQT syndrome has been reported at our laboratory (KCNQ1, c.1663C>T, p.Arg555Cys), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to abolish ability of ankyrin-B to restore abnormal calcium dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP3R in mouse cardiomyocytes (Mohler_2004). However, it is not evident how these outcomes correlate to incidence of disease in human. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x), uncertain significance (1x) and once as pathogenic. Based on the evidence outlined above, the variant was classified as benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001145853	SCV003920137	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2021-03-30	criteria provided, single submitter	clinical testing	ANK2 NM_001148.4 exon 45 p.Arg3906Trp (c.11716C>T): This variant has been reported in the literature in at least 7 individuals with syncope or clinical features of Long QT syndrome (Mohler 2004 PMID:15178757, Sherman 2005 PMID:16253912, Lieve 2013 PMID:2361430) as well as 1 infant with sudden death (Methner 2016 PMID:27435932). However, this variant is present in 0.1% (233/126380) of European alleles including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912706). This variant is present in ClinVar (Variation ID:18059). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies using mouse cardiomyocytes have shown that this variant may impact the protein, potentially affecting cytoplasmic calcium release events and contraction rates, and may cause a loss of function (Mohler 2007 PMID:17242276). However, further studies are needed to understand its impact. In summary, due to conflicting evidence for this variant, the clinical significance of this variant is uncertain.
OMIM	RCV000019676	SCV000039974	pathogenic	Long QT syndrome 4	2004-06-15	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV001841250	SCV000089871	not provided	Cardiac arrhythmia		no assertion provided	literature only	This variant has been reported as associated with Cardiac arrhythmia in the following publications (PMID:15178757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences	RCV000234999	SCV000263109	pathogenic	Death in infancy	2015-03-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904850	SCV004726408	likely benign	ANK2-related disorder	2023-02-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).