Submissions for variant NM_001148.6(ANK2):c.6228G>T (p.Lys2076Asn)

gnomAD frequency: 0.00050  dbSNP: rs144848998

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171742	SCV000055257	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Invitae	RCV001085787	SCV000545137	likely benign	Long QT syndrome	2024-01-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000171742	SCV001154245	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	ANK2: BP4
Illumina Laboratory Services, Illumina	RCV001147448	SCV001308274	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000171742	SCV001713314	uncertain significance	not provided	2019-09-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000171742	SCV001825729	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing	Reported in one family with primary electrical disease, in an infant deceased from SIDS, and in an individual with Emery-Dreifuss muscular dystrophy (Neubauer et al., 2017; Proost et al., 2017; Meinke et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28341588, 28074886, 31862442)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307431	SCV002600540	likely benign	not specified	2022-10-17	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.6228G>T (p.Lys2076Asn) 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 0.00033 in 250964 control chromosomes, predominantly at a frequency of 0.00064 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 64-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.6228G>T has been reported in the literature in individuals affected with Primary electrical disease, Sudden infant death syndrome and Emery-Dreifuss muscular dystrophy (Neubauer_2017, Proost_2017, Meinke_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002362876	SCV002659419	likely benign	Cardiovascular phenotype	2018-04-18	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.
Dept of Medical Biology, Uskudar University	RCV001085787	SCV004022082	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV003447513	SCV004174883	uncertain significance	Congenital long QT syndrome	2023-12-01	criteria provided, single submitter	clinical testing	Heterozygous variant NM_001148:c.6228G>T (p.Lys2076Asn) in the ANK2 gene was found on WES data in female proband (13 y.o., Caucasian) with Long QT syndrome. Additional rare candidate variant NM_000891:c.1222C>G (p.Leu408Val) (Class III of pathogenicity) in the KCNJ2 gene was found in this proband. The NM_001148:c.6228G>T variant is in The Genome Aggregation Database (gnomAD) v2.1.1 and v4.0.0 with total MAF 0.0004108 and 0.0003996 respectively (Date of access 01-12-2023). Clinvar contains an entry for this variant (Variation ID: 191538). This variant has been reported in 3 studies in patients with variable phenotypes (PMID: 28074886, 28341588, 31862442). Most in silico predictors show benign result of the protein change (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: BP4.