Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_001148.6(ANK2):c.2852C>T(p.Thr951Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T951A) has been classified as Uncertain significance.
ANK2 (HGNC:493): (ankyrin 2) This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. The protein encoded by this gene is required for targeting and stability of Na/Ca exchanger 1 in cardiomyocytes. Mutations in this gene cause long QT syndrome 4 and cardiac arrhythmia syndrome. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2011]
Uncertain significance, criteria provided, single submitter
clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Nov 03, 2021
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Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Oct 19, 2016
In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs773635091, ExAC 0.003%) but has not been reported in the literature in individuals with a ANK2-related disease. This sequence change replaces threonine with isoleucine at codon 951 of the ANK2 protein (p.Thr951Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -