ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.7249G>C (p.Asp2417His)

gnomAD frequency: 0.00001  dbSNP: rs372545180
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493998 SCV000582261 uncertain significance not provided 2017-05-04 criteria provided, single submitter clinical testing The D2417H variant has not been publishedas pathogenic or been reported as benign to our knowledge. Furthermore, it is not observed at a significant frequencyin large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). TheD2417H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structureas these residues differ in polarity, charge, size and/or other properties. Moreover, although this substitution occurs ata position that is not conserved across species, in silico analysis predicts this variant is probably damaging to theprotein structure/function. Nonetheless, this variant lacks observation in a significant number of affected individuals,segregation data, and functional evidence, which would further clarify its pathogenicity.
Ambry Genetics RCV002376905 SCV002671961 likely benign Cardiovascular phenotype 2021-07-19 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.
Invitae RCV002524032 SCV003482019 uncertain significance Long QT syndrome 2022-04-15 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 2417 of the ANK2 protein (p.Asp2417His). This variant is present in population databases (rs372545180, gnomAD 0.0009%). 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: 429643). 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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