ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.10976G>T (p.Arg3659Leu) (rs556640912)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443671 SCV000512041 uncertain significance not provided 2015-09-07 criteria provided, single submitter clinical testing A variant of unknown significance has been identified in the ANK2 gene. The R3659L variant has been observed in one individual referred for LQTS testing and was absent from 600 control alleles; however, no additional clinical information or segregation analysis was provided (Lieve et al., 2013). Although the R3659L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, the 1000 Genomes Project reports R3659L was observed in 2/978 (0.2%) alleles from individuals of South Asian background. Additionally, this substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants. Nevertheless, the R3659L 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 a pathogenic variant or a rare benign variant.
Invitae RCV001078512 SCV001007467 likely benign Long QT syndrome 2020-11-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290572 SCV001478648 benign not specified 2021-01-28 criteria provided, single submitter clinical testing Variant summary: ANK2 c.10976G>T (p.Arg3659Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251170 control chromosomes, predominantly at a frequency of 0.00098 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 147-fold the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome phenotype (6.7e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.10976G>T has been reported in the literature in individuals affected with Long QT Syndrome (e.g. Lieve_2013, Proost_2017). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. Co-occurrence with another pathogenic variant has been reported (SCN5A c.3995C>T, p.Pro1332Leu; Lieve_2013), providing supporting evidence for a benign role. 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. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

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