Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002316052 | SCV000847478 | uncertain significance | Inborn genetic diseases | 2016-08-05 | criteria provided, single submitter | clinical testing | The p.H2220P variant (also known as c.6659A>C), located in coding exon 46 of the CACNA1A gene, results from an A to C substitution at nucleotide position 6659. The histidine at codon 2220 is replaced by proline, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5147 samples (10294 alleles) with coverage at this position. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001348039 | SCV001542325 | uncertain significance | Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2220 of the CACNA1A protein (p.His2220Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 588132). 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. 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. |
| Centre de Biologie Pathologie Génétique, |
RCV001251915 | SCV001427661 | likely benign | Intellectual disability | 2019-01-01 | no assertion criteria provided | clinical testing |