Submissions for variant NM_001148.6(ANK2):c.8140G>A (p.Val2714Ile)

dbSNP: rs753223319

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432217	SCV000532477	uncertain significance	not provided	2016-10-07	criteria provided, single submitter	clinical testing	The V2714I novel variant of uncertain significance in the ANK2 gene has not been published as a pathogenic or benign variant to our knowledge. This variant was not observed in approximately 6,500 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 V2714I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution also occurs at a position that is not conserved, and I2714 is present in at least one species. Although in silico analysis is inconsistent in its predictions, the majority of in silico tools predict the V2714I variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001370715	SCV001567243	uncertain significance	Long QT syndrome	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2714 of the ANK2 protein (p.Val2714Ile). This variant is present in population databases (rs753223319, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 389821). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
New York Genome Center	RCV001542444	SCV001761150	uncertain significance	See cases	2020-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002418322	SCV002681745	likely benign	Cardiovascular phenotype	2023-03-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002506071	SCV002816154	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2021-12-27	criteria provided, single submitter	clinical testing