ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.6854T>C (p.Ile2285Thr) (rs150684838)

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Total submissions: 5
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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 RCV000171743 SCV000050742 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171743 SCV000532693 uncertain significance not provided 2018-06-18 criteria provided, single submitter clinical testing The I2285T variant in the ANK2 gene was reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing and was classified as likely not pathogenic" (Ng et al., 2013). In addition, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, the I2285T variant was observed in 29/124656 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the I2285T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties."
Invitae RCV000688226 SCV000815829 uncertain significance Long QT syndrome 2020-08-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2285 of the ANK2 protein (p.Ile2285Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs150684838, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with ANK2-related disease. ClinVar contains an entry for this variant (Variation ID: 191539). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852971 SCV000995720 likely benign Cardiomyopathy 2017-03-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000171743 SCV001154251 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing

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