Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000498887 | SCV000590590 | uncertain significance | not provided | 2017-06-20 | criteria provided, single submitter | clinical testing | The E69A variant in the NPPA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E69A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E69A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E69A as a variant of uncertain significance. |
Invitae | RCV001308826 | SCV001498297 | uncertain significance | Atrial fibrillation, familial, 6 | 2022-10-17 | criteria provided, single submitter | clinical testing | 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 432823). This variant has not been reported in the literature in individuals affected with NPPA-related conditions. This variant is present in population databases (rs376184349, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 69 of the NPPA protein (p.Glu69Ala). |