ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.4310C>T (p.Thr1437Met) (rs142534126)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250831 SCV000318341 uncertain significance Cardiovascular phenotype 2013-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
GeneDx RCV000170701 SCV000223254 likely pathogenic not provided 2014-03-04 criteria provided, single submitter clinical testing p.Thr1437Met (ACG>ATG): c.4310 C>T in exon 35 of the ANK2 gene (NM_001148.4). The T1437M variant in the ANK2 gene was reported in an alternate transcript as T1404I (4211 to 4212CG-TA). However, the NM number for the transcript was not provided. Functional studies demonstrated that the T1404I variant resulted in a negligible loss of function in cardiomyocytes (Mohler et al., 2007).The T1437M 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. T1437M is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. In silico algorithms are not consistent in their predictions, however two concur T1437M is damaging to the protein structure/function. However, the T1437 residue is not highly conserved across species and only one mutation in a nearby residue (G1439C) has been reported in association with LQTS. Therefore, this variant is a strong candidate for a pathogenic mutation. However, the possibility it is a benign variant cannot be excluded. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000698260 SCV000826915 uncertain significance Long QT syndrome 2018-08-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1437 of the ANK2 protein (p.Thr1437Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs142534126, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant was reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant is also known as c.4283C>T:p.T1428M in the literature.  ClinVar contains an entry for this variant (Variation ID: 190571). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000170701 SCV000924746 uncertain significance not provided 2015-12-16 no assertion criteria provided provider interpretation

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