ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.10861C>G (p.Leu3621Val)

gnomAD frequency: 0.00284  dbSNP: rs45570339
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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 RCV000171796 SCV000055261 benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
GeneDx RCV000170658 SCV000223211 benign not specified 2018-03-12 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000171796 SCV000286227 benign Long QT syndrome 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618704 SCV000735406 likely benign Cardiovascular phenotype 2018-12-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000170658 SCV000918421 benign not specified 2018-12-20 criteria provided, single submitter clinical testing Variant summary: ANK2 c.10861C>G (p.Leu3621Val) results in a conservative amino acid change located in the Death domain of the encoded protein sequence (InterPro). Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00091 in 276772 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0097 in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 970 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services,Illumina RCV001150176 SCV001311189 likely benign Cardiac arrhythmia, ankyrin-B-related 2017-04-28 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001705712 SCV001471088 uncertain significance not provided 2019-12-27 criteria provided, single submitter clinical testing The ANK2 c.10861C>G, p.Leu3621Val variant (rs45570339) is reported in the literature in one individual affected with long QT syndrome (Sherman 2005). This variant is found in the African population with an allele frequency of 0.9% (239/24,958 alleles, including 1 homozygote) in the Genome Aggregation Database. The leucine at codon 3621 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2:probably damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Leu3621Val variant is uncertain at this time. References: Sherman et al. Targeted mutational analysis of ankyrin-B in 541 consecutive, unrelated patients referred for long QT syndrome genetic testing and 200 healthy subjects. Heart Rhythm. 2005 Nov;2(11):1218-23. Gene statement: Pathogenic variants in ANK2 are associated with autosomal dominant ankyrin-B-related cardiac arrhythmia and long QT syndrome 4 (MIM: 600919).
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058342 SCV000089862 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:16253912). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Genetics, Academic Medical Center RCV001705712 SCV001917394 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001705712 SCV001927384 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001705712 SCV001975436 likely benign not provided no assertion criteria provided clinical testing

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