Submissions for variant NM_001148.6(ANK2):c.4745G>A (p.Arg1582Gln)

gnomAD frequency: 0.00090  dbSNP: rs138842207

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171739	SCV000050745	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Ambry Genetics	RCV000242956	SCV000319006	likely benign	Cardiovascular phenotype	2018-08-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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 Laboratory Services, Illumina	RCV000606830	SCV000447181	likely benign	Cardiac arrhythmia, ankyrin-B-related	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000360584	SCV000557178	likely benign	Long QT syndrome	2023-12-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000171739	SCV000729790	likely benign	not provided	2020-10-13	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000606830	SCV000743822	likely benign	Cardiac arrhythmia, ankyrin-B-related	2016-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000613422	SCV001361177	benign	not specified	2019-08-13	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.4745G>A (p.Arg1582Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 281862 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 150 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 Non-Finnish European origin. c.4745G>A has been reported in the literature to be found in 3 heterozygotes, and their average QTc value was reported to be in the normal range. (Ghouse_2015). This report therefore does not support a pathogenic role for the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four laboratories classified the variant as likely benign, while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000613422	SCV001433462	likely benign	not specified	2020-01-21	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000606830	SCV002525046	benign	Cardiac arrhythmia, ankyrin-B-related	2021-12-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000171739	SCV003799657	likely benign	not provided	2022-04-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000171739	SCV004148731	benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	ANK2: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003937538	SCV004755982	likely benign	ANK2-related condition	2022-02-12	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000606830	SCV000734303	likely benign	Cardiac arrhythmia, ankyrin-B-related		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000613422	SCV001917510	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000171739	SCV001955953	likely benign	not provided		no assertion criteria provided	clinical testing