ClinVar Miner

Submissions for variant NM_001148.4(ANK2):c.11218C>A (p.Leu3740Ile) (rs35530544)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000058346 SCV000885005 likely benign not provided 2018-03-20 criteria provided, single submitter clinical testing The c.11218C>A; p.Leu3740Ile variant was reported in a family with long QT syndrome, where it did not segregate with disease (Mohler 2004), and it was also detected in a single case among a cohort of sudden infant death syndrome cases, although the study authors classified it as unlikely to be pathogenic (Neubauer 2017). Studies of knock-in mice have linked this variant to a diabetic metabolic syndrome (Lorenzo 2015) and to cardiac arrhythmia and reduced ANK2 protein expression, prompting a proposed categorization as a “mild” loss-of-function allele (Musa 2016). This variant is listed in the genome Aggregation Database (gnomAD) with an African population frequency of 3.4% (identified on 817 out of 24,028 chromosomes, including 14 homozygotes), and is common in West African subpopulations in the 1000 Genomes Project (5.3% in the Gambian subpopulation). Based on the available information, the c.11218C>A; p.Leu3740Ile variant is likely to be benign.
Ambry Genetics RCV000242138 SCV000318511 benign Cardiovascular phenotype 2015-07-16 criteria provided, single submitter clinical testing
Biesecker Lab/Human Development Section,National Institutes of Health RCV000171797 SCV000050804 benign Cardiac arrhythmia 2013-06-24 criteria provided, single submitter research
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).
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
Illumina Clinical Services Laboratory,Illumina RCV000227575 SCV000447230 likely benign Long QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000058346 SCV000697722 likely benign not provided 2017-08-10 criteria provided, single submitter clinical testing Variant summary: The ANK2 c.11218C>A (p.Leu3740Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 399/122868 control chromosomes (7 homozygotes) at a frequency of 0.0032474, which is approximately 325 times the estimated maximal expected allele frequency of a pathogenic ANK2 variant (0.00001), suggesting this variant is likely a benign polymorphism. Variant was reported in multiple patients presenting with clinical phenotypes that often extended beyond the typical LQTS, including bradycardia, sinus arrhythmia, delayed conduction/conduction block, idiopathic ventricular fibrillation, SIDS, and catecholaminergic polymorphic ventricular tachycardia. Functional studies showed that this variant causes minor loss of function leading to less severe in vitro phenotypes and was hypothesized to likely be present in unaffected populations (Mohler_2004 and 2007) and as a mild loss-of-function variant that may confer arrhythmia susceptibility in the context of secondary risk factors including environment, medication, and/or additional genetic variation (Musa_2016). However, 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. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as likely benign.
Invitae RCV000227575 SCV000286229 benign Long QT syndrome 2018-01-03 criteria provided, single submitter clinical testing
OMIM RCV000019675 SCV000039973 pathogenic Cardiac arrhythmia, ankyrin B-related 2004-06-15 no assertion criteria provided literature only

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