ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.7546A>G (p.Ser2516Gly)

gnomAD frequency: 0.00001  dbSNP: rs771826064
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000696096 SCV000824643 uncertain significance Long QT syndrome 2021-04-14 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 2516 of the ANK2 protein (p.Ser2516Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. 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. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ANK2-related disease. This variant is present in population databases (rs771826064, ExAC 0.002%).
GeneDx RCV001775966 SCV002013121 uncertain significance not provided 2020-09-16 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, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 574222; Landrum et al., 2016); Located in exon 38 which is expressed in brain-specific ANK2 transcripts; no pathogenic variants in exon 38 have been reported in association with cardiac phenotypes to our knowledge
Ambry Genetics RCV002388264 SCV002674042 likely benign Cardiovascular phenotype 2020-11-25 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.

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