Submissions for variant NM_001148.6(ANK2):c.9046G>A (p.Glu3016Lys)

gnomAD frequency: 0.00052  dbSNP: rs149963885

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171747	SCV000050750	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Invitae	RCV001081980	SCV000286265	likely benign	Long QT syndrome	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000171747	SCV000517009	likely benign	not provided	2021-05-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 25351510, 28750076)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000171747	SCV000602493	likely benign	not provided	2023-10-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620867	SCV000737717	likely benign	Cardiovascular phenotype	2018-01-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000171747	SCV000987401	likely benign	not provided		criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852975	SCV000995724	likely benign	Cardiomyopathy	2017-03-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001150060	SCV001311068	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440096	SCV001363530	likely benign	not specified	2019-11-25	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.9046G>A (p.Glu3016Lys) 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 0.00058 in 250748 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 120 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 Latino origin. The variant, c.9046G>A, has been reported in the literature in individuals affected with hypertrophic or dilated cardiomyopathy, without supportive evidence for causality (Lopes_2015, Forleo_2017), and was also found in an unaffected individual, who had no ECG signs of Long QT Syndrome (Ghouse_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Dept of Medical Biology, Uskudar University	RCV001081980	SCV004021954	likely benign	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, BP4
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000171747	SCV000924736	likely benign	not provided	2017-09-05	no assertion criteria provided	provider interpretation	p.Glu3016Lys (c.9046G>A) in the ANK2 gene (NM_001148.4) Seen in tandem with a pathogenic variant in a gene that better fits the patient's phenotype (arrhythmic DCM). Given the weak case data and frequency in the general population, we consider this to be likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 1 case of hypertrophic cardiomyopathy (HCM) (not including this patient's family), however the case data is weak. The variant was detected in a heterozygous state in one patient from a study in which 41 genes implicated in cardiac disease were sequenced in 874 patients with HCM (PMID 25351510). There is no information about this specific patient or his/her family, therefore whether or not this variant was disease-causing in this case is not possible to assess. In silico models do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0") (source: lab report). The glutamic acid at codon 3016 is highly conserved and there is a small physicochemical difference between glutamic acid and lysine (source: lab report). In the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), it is present in 59 of ~64,000 individuals of European, African, Latino and Asian descent (as of 1/25/16).
Clinical Genetics, Academic Medical Center	RCV000171747	SCV001925240	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000171747	SCV001930664	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000171747	SCV001966417	likely benign	not provided		no assertion criteria provided	clinical testing