ClinVar Miner

Submissions for variant NM_001148.4(ANK2):c.4373A>G (p.Glu1458Gly) (rs72544141)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244762 SCV000318832 uncertain significance Cardiovascular phenotype 2018-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Deficient protein function in appropriate functional assay(s),Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Biesecker Lab/Human Development Section,National Institutes of Health RCV000171737 SCV000050744 likely benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
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.
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.
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
HudsonAlpha Institute for Biotechnology RCV000019673 SCV000584065 likely pathogenic Cardiac arrhythmia, ankyrin B-related 2015-11-12 criteria provided, single submitter research
Invitae RCV000171737 SCV000286249 likely benign Long QT syndrome 2017-12-27 criteria provided, single submitter clinical testing
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, http://exac.broadinstitute.org; 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.
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

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