ClinVar Miner

Submissions for variant NM_001148.4(ANK2):c.2060A>G (p.Asn687Ser) (rs29372)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Human Development Section,National Institutes of Health RCV000171786 SCV000050797 benign not specified 2013-06-24 criteria provided, single submitter research
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477910 SCV000536759 uncertain significance Cardiac arrhythmia, ankyrin B-related 2015-12-10 no assertion criteria provided research
GeneDx RCV000171786 SCV000223281 uncertain significance not specified 2015-07-20 criteria provided, single submitter clinical testing p.Asn687Ser (AAT>AGT): c.2060 A>G in exon 18 of the ANK2 gene (NM_001148.4). Mank-Seymour et al. reported the N687S variant as a polymorphism, however, clinical information was not provided (Mank-Seymour et al., 2006). The N687S 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, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. However, the N687S 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, indicating it is not a common benign variant in these populations. Additionally, this substitution occurs at a position that is conserved among mammals. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000700217 SCV000828965 uncertain significance Long QT syndrome 2018-03-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 687 of the ANK2 protein (p.Asn687Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs29372, ExAC 0.02%). This variant has not been reported in the literature in individuals with ANK2-related disease. ClinVar contains an entry for this variant (Variation ID: 190594). 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 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.

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