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

gnomAD frequency: 0.01031  dbSNP: rs35530544

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV001841249	SCV000050804	benign	Cardiac arrhythmia	2013-06-24	criteria provided, single submitter	research
Invitae	RCV000227575	SCV000286229	benign	Long QT syndrome	2024-01-22	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: 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.
Illumina Laboratory Services, 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	RCV000058346	SCV000885005	benign	not provided	2023-09-21	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)
Genome-Nilou Lab	RCV000019675	SCV002525095	benign	Cardiac arrhythmia, ankyrin-B-related	2021-12-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000019675	SCV002809622	benign	Cardiac arrhythmia, ankyrin-B-related	2022-04-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000058346	SCV004148764	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ANK2: BP4, BS1, BS2
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).