Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000422038 | SCV000524481 | uncertain significance | not provided | 2016-11-01 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the CACNA1A gene. The K2204R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 5,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species; however, Arginine is observed at this position in evolution. The K2204R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Fulgent Genetics, |
RCV000764174 | SCV000895176 | uncertain significance | Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002521655 | SCV003459724 | uncertain significance | Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 | 2022-03-13 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1A protein function. ClinVar contains an entry for this variant (Variation ID: 383881). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2204 of the CACNA1A protein (p.Lys2204Arg). |