Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000170843 | SCV000223398 | uncertain significance | not provided | 2018-09-12 | criteria provided, single submitter | clinical testing | The Asp1099Asn variant in the CACNA1C gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Asp1099Asn results in a non-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral, polar Asparagine at a residue that is conserved across species. Additionally, the Asp1099Asn variant was not detected in up to 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. In silico analysis predicts Asp1099Asn is possibly damaging to the protein structure/function. However, Asp1099Asn is located in a region of the CACNA1C gene with few reported mutations, suggesting this region of the protein may be tolerant of change. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine whether the Asp1099Asn variant is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). |
| Invitae | RCV000687893 | SCV000815485 | uncertain significance | Long QT syndrome | 2022-08-31 | 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 190704). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is present in population databases (rs771549676, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1099 of the CACNA1C protein (p.Asp1099Asn). |
| Ambry Genetics | RCV002321682 | SCV002611179 | likely benign | Cardiovascular phenotype | 2021-11-17 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |