Submissions for variant NM_001148.6(ANK2):c.4744C>T (p.Arg1582Trp)

gnomAD frequency: 0.00403  dbSNP: rs35249198

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171787	SCV000050798	benign	not specified	2013-06-24	criteria provided, single submitter	research
Invitae	RCV000157108	SCV000260827	benign	Long QT syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094874	SCV000447180	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.
GeneDx	RCV000171787	SCV000516867	benign	not specified	2016-12-13	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.
Ambry Genetics	RCV000621628	SCV000735007	benign	Cardiovascular phenotype	2016-10-23	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000171787	SCV000918427	benign	not specified	2018-03-06	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.4744C>T (p.Arg1582Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 278208 control chromosomes in the gnomAD database, predominantly within the Finnish subpopulation at a frequency of 0.01, including 2 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 1000 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. c.4744C>T has been reported in the literature in heterozygosity in healthy individuals without arrhythmia or elongation of the QT interval (Ghouse 2015). This report provides further support about the benign nature of the variant. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, classifying the variant as benign(2)/VUS(1). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001094874	SCV002525045	benign	Cardiac arrhythmia, ankyrin-B-related	2021-12-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003430716	SCV004148730	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ANK2: BP4, BS2
Blueprint Genetics	RCV000157108	SCV000206831	likely benign	Long QT syndrome	2014-05-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000171787	SCV001919031	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000171787	SCV001928798	benign	not specified		no assertion criteria provided	clinical testing