ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.8892C>G (p.Ile2964Met) (rs62313245)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000242675 SCV000320028 likely benign Cardiovascular phenotype 2019-12-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Illumina Clinical Services Laboratory,Illumina RCV000764528 SCV000447211 uncertain significance Cardiac arrhythmia, ankyrin B-related 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000487226 SCV000568993 uncertain significance not provided 2018-07-17 criteria provided, single submitter clinical testing The I2964M variant of uncertain significance in the ANK2 gene has not been published as pathogenic or been reported as benign to our knowledge. It has been observed both independently, and in conjunction with another cardiogenetic variant, in other individuals referred for arrhythmia genetic testing at GeneDx, although no segregation data are available. The I2964M is observed in 39/276744 (0.01%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The I2964M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000285338 SCV000627681 uncertain significance Long QT syndrome 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 2964 of the ANK2 protein (p.Ile2964Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs62313245, ExAC 0.03%) but has not been reported in the literature in individuals with an ANK2-related disease. ClinVar contains an entry for this variant (Variation ID: 264239). 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: Possibly Damaging; Align-GVGD: Class C0). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000764528 SCV000895611 uncertain significance Cardiac arrhythmia, ankyrin B-related 2018-10-31 criteria provided, single submitter clinical testing

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