ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.4456G>C (p.Val1486Leu) (rs149678604)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253621 SCV000318917 likely benign Cardiovascular phenotype 2018-11-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000437323 SCV000512040 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing The V1486L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1486L variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, V1486L is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to valine are tolerated across species, including L1486 which is wildtype in at least one non-mammalian species. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000477573 SCV000545124 uncertain significance Long QT syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 1486 of the ANK2 protein (p.Val1486Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs149678604, ExAC 0.03%) but has not been reported in the literature in individuals with a ANK2-related disease. ClinVar contains an entry for this variant (Variation ID: 263709). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000764525 SCV000895608 uncertain significance Cardiac arrhythmia, ankyrin B-related 2018-10-31 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000437323 SCV000987637 uncertain significance not provided criteria provided, single submitter clinical testing

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