ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.1177G>A (p.Ala393Thr) (rs147458476)

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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/Clinical Genomics Section,National Institutes of Health RCV000171736 SCV000055182 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171736 SCV000583306 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ANK2 gene. The A393T variant has not been previously published in association with arrhythmia to our knowledge. However, it has been observed in one individual from a cohort of individuals not selected for a history of cardiomyopathy, arrhythmia or family history of sudden cardiac death who underwent exome sequencing (Ng et al., 2013). Additionally, this variant has been observed in 8/8624 (0.09%) alleles from individuals of African ancestry, and 11/66346 (0.02%) alleles from individuals of Non-Finnish European ancestry, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Nevertheless, the A393T 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, this substitution occurs at a position that is largely conserved across species, although threonine (T) is the wild-type residue at this position in one non-mammalian species.
Ambry Genetics RCV000621489 SCV000735831 uncertain significance Cardiovascular phenotype 2017-03-29 criteria provided, single submitter clinical testing The p.A393T variant (also known as c.1177G>A), located in coding exon 11 of the ANK2 gene, results from a G to A substitution at nucleotide position 1177. The alanine at codon 393 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in an individual undergoing clinical long QT syndrome (LQTS) genetic testing and reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited. (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species; however, threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001050790 SCV001214914 uncertain significance Long QT syndrome 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 393 of the ANK2 protein (p.Ala393Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs147458476, ExAC 0.09%). This variant has been observed in individual(s) with clinical features of long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 191533). 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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