Submissions for variant NM_001148.6(ANK2):c.9454A>G (p.Thr3152Ala)

gnomAD frequency: 0.00340  dbSNP: rs61741040

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171793	SCV000055259	benign	not specified	2013-06-24	criteria provided, single submitter	research
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224811	SCV000280655	likely benign	not provided	2016-04-08	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Invitae	RCV000226208	SCV000286269	benign	Long QT syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094764	SCV000447215	likely benign	Cardiac arrhythmia, ankyrin-B-related	2018-01-13	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	RCV000171793	SCV000518474	benign	not specified	2017-01-13	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	RCV000619796	SCV000735653	benign	Cardiovascular phenotype	2016-05-25	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000171793	SCV000918445	benign	not specified	2018-09-17	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.9454A>G (p.Thr3152Ala) results in a non-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 0.0011 in 276106 control chromosomes, predominantly at a frequency of 0.011 within the African subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 1100-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 African origin. To our knowledge, no occurrence of c.9454A>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Five 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852976	SCV000995725	benign	Primary dilated cardiomyopathy	2019-05-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224811	SCV001472949	benign	not provided	2022-06-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001094764	SCV002525080	benign	Cardiac arrhythmia, ankyrin-B-related	2021-12-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224811	SCV004148757	benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	ANK2: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003965230	SCV004777487	benign	ANK2-related condition	2022-03-16	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).