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

dbSNP: rs147706514

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000243394	SCV000320143	likely benign	Cardiovascular phenotype	2021-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1744 of the ANK2 protein (p.Ala1744Asp). This variant is present in population databases (rs147706514, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23396983). ClinVar contains an entry for this variant (Variation ID: 264303). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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