ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.9916G>A (p.Val3306Ile)

gnomAD frequency: 0.00006  dbSNP: rs200922244
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171607 SCV000055260 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171607 SCV001758838 uncertain significance not provided 2021-06-28 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Located in exon 38, which is reported as being expressed in a brain-specific transcript (Otto et al, 1991; Cunha et al, 2008; Wu et al, 2015); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 191415; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 26582918)
Ambry Genetics RCV002381550 SCV002695857 likely benign Cardiovascular phenotype 2019-10-02 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 RCV002505236 SCV002816790 uncertain significance Cardiac arrhythmia, ankyrin-B-related 2021-09-03 criteria provided, single submitter clinical testing
Invitae RCV002515244 SCV003295969 uncertain significance Long QT syndrome 2023-02-22 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 3306 of the ANK2 protein (p.Val3306Ile). This variant is present in population databases (rs200922244, gnomAD 0.003%). 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: 191415). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". 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.

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