ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.3931G>A (p.Val1311Ile) (rs34065266)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170698 SCV000223251 uncertain significance not provided 2013-01-26 criteria provided, single submitter clinical testing p.Val1311Ile (GTT>ATT): c.3931 G>A in exon 33 of the ANK2 gene (NM_001148.4). The Val1311Ile variant in the ANK2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Val1311Ile results in a conservative amino acid substitution of one non-polar amino acid for another, this substitution occurs at a position that is conserved across species. However, there have been no nearby mutations reported in association with LQTS, indicating this region of the protein may be tolerant of change. In silico analysis predicts Val1311Ile is possibly damaging to the protein structure/function. The Val1311Ile variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, however, the 1000 Genomes database reports it was present in 1/76 alleles (1.3%) from individuals of European ancestry.With the clinical and molecular information available at this time, we cannot definitively determine if Val1311Ile in the ANK2 gene is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000467208 SCV000545140 uncertain significance Long QT syndrome 2020-03-15 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1311 of the ANK2 protein (p.Val1311Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs34065266, ExAC 0.02%) but has not been reported in the literature in individuals with a ANK2-related disease. 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, 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.
Ambry Genetics RCV000619169 SCV000738243 uncertain significance Cardiovascular phenotype 2020-02-13 criteria provided, single submitter clinical testing The p.V1311I variant (also known as c.3931G>A), located in coding exon 33 of the ANK2 gene, results from a G to A substitution at nucleotide position 3931. The valine at codon 1311 is replaced by isoleucine, an amino acid with highly similar properties. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175061 SCV001338608 likely benign not specified 2020-04-27 criteria provided, single submitter clinical testing Variant summary: ANK2 c.3931G>A (p.Val1311Ile) results in a conservative amino acid change in 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 6.4e-05 in 251292 control chromosomes. The observed variant frequency is approximately 6.4- fold the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3931G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.