ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.4782T>G (p.Ile1594Met) (rs775386505)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489329 SCV000576675 uncertain significance not provided 2017-04-21 criteria provided, single submitter clinical testing The I1594M variant of uncertain significance in the ANK2 gene has not been published as pathogenic or been reported as benign to our knowledge. This substitution occurs at a position where only amino acids with similar properties to isoleucine are tolerated across species. However, the I1594M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the I1594M variant was observed in 21/11,540 alleles from individuals of Latino ancestry in the Exome Aggregation Consortium (ExAC) dataset, indicating it may be a rare benign variant in this population (Lek et al., 2016).
Ambry Genetics RCV000617304 SCV000735577 likely benign Cardiovascular phenotype 2017-04-07 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV001043339 SCV001207075 uncertain significance Long QT syndrome 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 1594 of the ANK2 protein (p.Ile1594Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs775386505, ExAC 0.2%). This variant has not been reported in the literature in individuals with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 426274). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.

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