ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.5231C>A (p.Ala1744Asp) (rs147706514)

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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 RCV000243394 SCV000320143 uncertain significance Cardiovascular phenotype 2019-04-19 criteria provided, single submitter clinical testing The p.A1744D variant (also known as c.5231C>A), located in coding exon 38 of the ANK2 gene, results from a C to A substitution at nucleotide position 5231. This exon is expressed solely in brain (Mohler PJ et al. Circulation. 2007;115(4):432-41). The alanine at codon 1744 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant has been reported in a hypertrophic cardiomyopathy cohort in an individual with variants in other cardiac-related genes (Lopes LR et al. J Med Genet. 2013;50(4):228-39; Lopes LR et al. Heart. 2015;101(4):294-301). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
GeneDx RCV000498222 SCV000589398 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ANK2 gene. The A1744D variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 22/125540 (0.0175%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nonetheless, the A1744D 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. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194188 SCV001363533 likely benign not specified 2019-05-27 criteria provided, single submitter clinical testing Variant summary: ANK2 c.5231C>A (p.Ala1744Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249916 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5231C>A has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (Lopes_2013). This report however, does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV001239833 SCV001412734 uncertain significance Long QT syndrome 2020-04-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 1744 of the ANK2 protein (p.Ala1744Asp). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs147706514, ExAC 0.01%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 23396983). ClinVar contains an entry for this variant (Variation ID: 264303). 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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252394 SCV001428149 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing

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