ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.4373A>G (p.Glu1458Gly) (rs72544141)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171737 SCV000050744 likely benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
GeneDx RCV000170702 SCV000223255 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing The E1458G variant in the ANK2 gene, described as E1425G due to the use of alternate nomenclature, has been previously reported in a large family with a history of LQTS or sinus node dysfunction (Mohler et al., 2003). In this study, 24 family members were identified to harbor the E1458G variant, and 23 of these 24 variant carriers had features of LQTS and/or sinus node dysfunction, demonstrating that E1458G segregated with disease in this family (Mohler et al., 2003). This variant has also been described in several individuals with sudden death/SIDS (Hertz et al., 2016; Sanchez et al., 2016; Lin et al., 2017; Neubauer et al., 2017) as well as in association with HCM (Lopes et al., 2013); however, additional cardiogenetic variants were reported in some of these probands. Similarly, while E1458G has been identified in multiple other unrelated individuals tested for LQTS at GeneDx, many probands harbored other cardiogenetic variants that likely contributed to their phenotype. Furthermore, E1458G has been reported in several individuals without a known history of cardiovascular disease (Ng et al., 2013; Ghouse et al., 2015 Vassy et al., 2017), and it has been observed in 0.08% (96/126,426) of alleles from individuals of European (non-Finnish) background as well as in 0.1% (38/34,338) of alleles from individuals of Latino background, including one homozygote, in large population cohorts (Lek et al., 2016). Nevertheless, functional studies demonstrated E1458G results in abnormal Ca2+ signaling in mouse cardiomyocytes, and mice heterozygous for the E1458G variant had a high incidence of sudden death after exercise and exposure to epinephrine (Mohler et al., 2003; Mohler et al., 2007). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000019673 SCV000245576 likely pathogenic Cardiac arrhythmia, ankyrin B-related 2014-12-22 criteria provided, single submitter clinical testing The p.Glu1458Gly variant (also referred to as p.Glu1425Gly) has been identified in >20 affected members of a large kindred with autosomal dominant long QT syndrome (Mohler 2003). It has been identified in an unaffected individual whose three siblings died suddenly at a young age (Mohler 2004). It has also been identified in 0.06% (41/67458) of European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs72544141). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro and in vivo functional studies in mice provide some evidence that the p.Glu1458Gly variant may impact protein function (Mohler 2003, Mohler 2004, Le Scouarnec 2008). In p.Glu1458Gly variant is likely pathogenic.
Invitae RCV000171737 SCV000286249 likely benign Long QT syndrome 2020-11-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000244762 SCV000318832 uncertain significance Cardiovascular phenotype 2020-03-16 criteria provided, single submitter clinical testing The p.E1458G variant (also known as c.4373A>G), located in coding exon 36 of the ANK2 gene, results from an A to G substitution at nucleotide position 4373. The glutamic acid at codon 1458 is replaced by glycine, an amino acid with similar properties. Also reported as p.E1425G (c.4274A>G) in the literature, this variant was shown to segregate with long QT syndrome (LQTS) and sinus node dysfunction in a large kindred (Mohler PJ et al. Nature. 2003; 421(6923):634-9). Functional assays by the same group demonstrated that this alteration disrupts ANK2 function (e.g., Mohler PJ et al. Nature. 2003;421(6923):634-9; Mohler PJ et al. Circulation. 2007;115(4):432-41). More recently, this variant was detected multiple times in a healthy Danish exome cohort, with no significant effect on QT interval (Ghouse J et al. Eur Heart J. 2015;36(37):2523-9). This alteration was also observed in a hypertrophic cardiomyopathy cohort and an exome cohort; however, clinical details were limited (Lopes LR et al J Med Genet. 2013;50(4):228-39; Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). Based on data from gnomAD, the G allele has an overall frequency of approximately 0.053% (151/282480) total alleles studied, and one homozygote has been observed. The highest observed frequency was 0.116% (41/35360) of Latino alleles, which is higher than expected for the disease. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000019673 SCV000584065 likely pathogenic Cardiac arrhythmia, ankyrin B-related 2015-11-12 criteria provided, single submitter research
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000019673 SCV000743821 uncertain significance Cardiac arrhythmia, ankyrin B-related 2016-12-27 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845369 SCV000987427 uncertain significance Conduction disorder of the heart criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002092 SCV001159938 uncertain significance not specified 2018-10-01 criteria provided, single submitter clinical testing The ANK2 c.4373A>G; p.Glu1458Gly variant (rs72544141), also known as p.Glu1425Gly, is reported in the literature in individuals affected with Long QT syndrome, sinus node dysfunction, arrhythmia, sudden unexplained death, and hypertrophic cardiomyopathy (Hertz 2016, Le Scouarnec 2008, Lin 2017. Lopes 2013, Mohler 2003, Neubauer 2017). In one large family, this variant segregated with long QT syndrome and sinus node dysfunction in more than 20 affected individuals and was not observed in any unaffected individuals (Le Scouarnec 2008, Mohler 2003). However, this variant was also observed in a healthy individual with normal QT interval (Mohler 2004), and it was not significantly associated with longer QT interval in a large Dutch cohort (Ghouse 2015). Further, the p.Glu1458Gly variant is found in the Latino population with an overall allele frequency of 0.11% (38/24226 alleles, including one homozygote) in the Genome Aggregation Database, and this population frequency exceeds the estimated prevalence of Long QT syndrome at 1 in 2000 (Lin 2017). In mouse cardiomyocytes lacking one copy of ANK2, transfection of the p.Glu1458Gly variant fails to rescue decreased spontaneous contraction rate to the same extent as wildtype protein (Mohler 2003, Mohler 2007). The glutamate at codon 1458 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to conflicting information, the clinical significance of the p.Glu1458Gly variant is uncertain at this time. References: Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Hertz CL et al. Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases. Eur J Hum Genet. 2016 Jun;24(6):817-22. Le Scouarnec S et al. Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15617-22. Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6). Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Mohler PJ et al. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9137-42. Mohler PJ et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003 Feb 6;421(6923):634-9. Mohler PJ et al. Defining the cellular phenotype of ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation. 2007 Jan 30;115(4):432-41. Neubauer J et al. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet. 2017 Apr;25(4):404-409. "
OMIM RCV000019672 SCV000039970 pathogenic Long QT syndrome 4 2004-06-15 no assertion criteria provided literature only
OMIM RCV000019673 SCV000039971 pathogenic Cardiac arrhythmia, ankyrin B-related 2004-06-15 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058356 SCV000089876 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12571597;PMID:15178757;PMID:18832177). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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