ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.80A>C (p.Lys27Thr)

gnomAD frequency: 0.00004  dbSNP: rs769843073
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170724 SCV000223277 uncertain significance not provided 2012-02-02 criteria provided, single submitter clinical testing The Lys27Thr variant in the ANK2 gene has not been reported previously as a disease-causing mutation, nor as a benign polymorphism to our knowledge. Lys27Thr results in a semi-conservative amino acid substitution of a positively charged Lysine residue with a neutral, polar Threonine residue at a position that is conserved across species. The NHLBI ESP Exome Variant Server reports Lys27Thr was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no other mutations affecting this region of the ANK2 gene have been reported to date, suggesting this region may be tolerant to change. In summary, with the molecular and clinical information available, we cannot definitively determine whether Lys27Thr is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV000228758 SCV000286261 uncertain significance Long QT syndrome 2023-03-10 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANK2 protein function. ClinVar contains an entry for this variant (Variation ID: 190590). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 25650408). This variant is present in population databases (rs769843073, gnomAD 0.005%). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 27 of the ANK2 protein (p.Lys27Thr).
Ambry Genetics RCV002415720 SCV002679119 uncertain significance Cardiovascular phenotype 2023-10-27 criteria provided, single submitter clinical testing The p.K27T variant (also known as c.80A>C), located in coding exon 1 of the ANK2 gene, results from an A to C substitution at nucleotide position 80. The lysine at codon 27 is replaced by threonine, an amino acid with similar properties. This alteration was observed in one individual reported to have Brugada syndrome; however, clinical details were limited (Le Scouarnec S et al. Hum. Mol. Genet., 2015 May;24:2757-63). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002498851 SCV002794374 uncertain significance Cardiac arrhythmia, ankyrin-B-related 2021-08-30 criteria provided, single submitter clinical testing

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