ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.4016C>T (p.Pro1339Leu) (rs371357815)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170700 SCV000223253 uncertain significance not provided 2015-06-16 criteria provided, single submitter clinical testing p.Pro1339Leu (CCC>CTC): c.4016 C>T in exon 33 of the ANK2 gene (NM_001148.4). Although rare, mutations in the ANK2 gene have been reported previously in association with LQTS (Mohler P et al., 2003). The P1339L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The P1339L variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P1339L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. 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 LQT panel(s).
Invitae RCV000200456 SCV000254720 uncertain significance Long QT syndrome 2020-01-23 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1339 of the ANK2 protein (p.Pro1339Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant has not been reported in the literature in individuals with ANK2-related disease. ClinVar contains an entry for this variant (Variation ID: 190570). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260348 SCV001437285 likely benign not specified 2020-09-08 criteria provided, single submitter clinical testing Variant summary: ANK2 c.4016C>T (p.Pro1339Leu) results in a non-conservative amino acid change located in the Ankyrin, UPA domain (IPR040745) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251292 control chromosomes, predominantly at a frequency of 0.00018 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 27-fold of 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 Non-Finnish European origin. To our knowledge, no occurrence of c.4016C>T in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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