ClinVar Miner

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

gnomAD frequency: 0.00094  dbSNP: rs121912706
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Total submissions: 13
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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.
Invitae 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 ( 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.
PreventionGenetics, part of Exact Sciences RCV003904850 SCV004726408 likely benign ANK2-related disorder 2023-02-18 criteria provided, single submitter 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).
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

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