ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.11716C>T (p.Arg3906Trp) (rs121912706)

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Total submissions: 11
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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 RCV000171750 SCV000050754 likely benign Cardiac arrhythmia 2013-06-24 criteria provided, single submitter research
GeneDx RCV000211890 SCV000223217 uncertain significance not specified 2017-10-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ANK2 gene. The R3906W variant, also known as R1788W, R1812W, and R1821W due to the use of alternate transcripts, has been reported in multiple individuals in association with LQTS (Mohler et al., 2004a; Sherman et al., 2005; Lieve et al., 2013). The R3906W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, R3906W is located within the ankyrin-B regulatory domain (Mohler et al., 2004b), at a position where only amino acids with similar properties to Arginine are tolerated across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that R3906W impairs spontaneous contraction rates, calcium dynamics, and the localization and expression of the Na/Ca exchanger, Na/K ATPase, and InsP3 receptor in mouse cardiomyocytes (Mohler et al., 2004a; Mohler et al., 2007a). Nevertheless, it remains to be determined how these functional studies in mice translate to human disease. Furthermore, the 1000 Genomes Project, the NHLBI Exome Sequencing Project, and the Exome Aggregation Consortium report R3906W was observed in approximately 0.14-0.20% of alleles from individuals of European background, indicating it may be a rare benign variant in this population. Moreover, R3906W has been found at a frequency of approximately 0.06-0.50% in multiple other control populations and/or populations not selected for a cardiac phenotype (Sherman et al., 2005; Mohler et al., 2007b; Ng et al. 2013). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV001082560 SCV000557197 likely benign Long QT syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620379 SCV000737448 likely benign Cardiovascular phenotype 2018-06-29 criteria provided, single submitter clinical testing Other strong data supporting benign classification
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 Praxis fuer Humangenetik Tuebingen RCV000474063 SCV001154266 uncertain significance not provided 2019-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
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 RCV000058351 SCV000089871 not provided 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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