ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.11218C>A (p.Leu3740Ile) (rs35530544)

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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 RCV000171797 SCV000050804 benign Cardiac arrhythmia 2013-06-24 criteria provided, single submitter research
Invitae RCV000227575 SCV000286229 benign Long QT syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000242138 SCV000318511 benign Cardiovascular phenotype 2015-07-16 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Illumina Clinical Services Laboratory,Illumina RCV000019675 SCV000447230 likely benign 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. 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000058346 SCV000609798 likely benign not provided 2017-05-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001580447 SCV000697722 benign not specified 2021-08-16 criteria provided, single submitter clinical testing Variant summary: ANK2 c.11218C>A (p.Leu3740Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 252716 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 245 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 benign. c.11218C>A has been reported in the literature in sequencing studies of individuals affected with Arrhythmic/SIDS/cardiac phenotypes without strong evidence of causality (example, Mohler_2004, Sherman_2005, Ng_2013, Methner_2016, Neubauer_2017). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a mild loss-of-function that may confer arrhythmia susceptibility in the context of secondary risk factors including environment,medication,and/or additional genetic variation (example, Musa_2016). However, to our knowledge, no large scale case control studies reporting the odds ratio (OR) and relative risk for an association of this variant with phenotypes of Arrythmia have been reported at present. Therefore, the exact consequences of these findings in settings of a penetrant and inheritable arrythmic phenotype is not substantiated. Six 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999933 SCV000885005 benign none provided 2020-08-23 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852981 SCV000995730 benign Cardiomyopathy 2019-02-16 criteria provided, single submitter clinical testing
GeneDx RCV000058346 SCV001858183 benign not provided 2018-11-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28074886, 27298202, 26168218, 15178757, 22995991)
OMIM RCV000019675 SCV000039973 pathogenic Cardiac arrhythmia, ankyrin B-related 2004-06-15 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058346 SCV000089866 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:15178757).

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