Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000317331 | SCV000330709 | pathogenic | not provided | 2016-07-20 | criteria provided, single submitter | clinical testing | The C1369R pathogenic variant in the CACNA1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. A variant at the same residue, C1369Y (also reported as C1370Y due to alternate nomenclature), has been reported in an individual with tremor of the head and hands, epilepsy, migraine without aura, and cerebellar atrophy (Geerlings et al., 2011). The C1369Y variant was also reported in a family with familial hemiplegic migraine. However, the variant did not completely segregate with disease in the family, as the variant was only present in 3 out of 4 affected individuals (Thomsen et al., 2007). The C1369R variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C1369R 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C1369R as a pathogenic variant. |
Invitae | RCV000802158 | SCV000941976 | uncertain significance | Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 | 2023-02-10 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1369 of the CACNA1A protein (p.Cys1369Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 280762). 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 expected to disrupt CACNA1A protein function. 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. |