Total submissions: 20
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Dasa | RCV000406556 | SCV007599691 | pathogenic | not provided | 2025-10-07 | criteria provided, single submitter | clinical testing | NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln) is a missense variant that results in the substitution of arginine with glutamine. De novo occurrence has been reported in an individual with related phenotype. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 28742085; PMID: 38681507; PMID: 34068417; PMID: 31475473; PMID: 35982159). This variant has been recurrently observed in individuals with related phenotype (PMID: 28742085; PMID: 38681507; PMID: 34068417; PMID: 31475473; PMID: 35982159). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. |
| Juno Genomics, |
RCV006605215 | SCV005418671 | pathogenic | Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42 | criteria provided, single submitter | clinical testing | Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. | |
| Pediatric Department, |
RCV003152591 | SCV003930353 | pathogenic | Developmental and epileptic encephalopathy, 42 | 2021-01-07 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV003152591 | SCV003841799 | pathogenic | Developmental and epileptic encephalopathy, 42 | 2025-01-22 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068432 /PMID: 16325861 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 28742085). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16325861, 28742085). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Baylor Genetics | RCV003152591 | SCV003841211 | pathogenic | Developmental and epileptic encephalopathy, 42 | criteria provided, single submitter | clinical testing | ||
| Revvity Omics, |
RCV000406556 | SCV003813096 | pathogenic | not provided | 2023-09-12 | criteria provided, single submitter | clinical testing | |
| Centre de Biologie Pathologie Génétique, |
RCV002273953 | SCV002559122 | pathogenic | Neurodevelopmental delay | criteria provided, single submitter | clinical testing | ||
| Ambry Genetics | RCV002311540 | SCV000846881 | pathogenic | Inborn genetic diseases | 2025-02-12 | criteria provided, single submitter | clinical testing | The p.R1664Q variant (also known as c.4991G>A), located in coding exon 32 of the CACNA1A gene, results from a G to A substitution at nucleotide position 4991. The arginine at codon 1664 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with CACNA1A-related neurologic disorder; in at least one individual, it was determined to be de novo (Raslan IR et al. Neurol Genet, 2024 Jun;10:e200153; Kessi M et al. Front Mol Neurosci, 2023 Jul;16:1222321; Martínez-Monseny AF et al. Int J Mol Sci, 2021 May;22:; Luo X et al. PLoS Genet, 2017 Jul;13:e1006905; Tonelli A et al. J. Neurol. Sci., 2006 Feb;241:13-7; Ambry internal data). The p.R1664Q amino acid is located in the voltage sensing domain. The variant disrupts the R2 position of the voltage sensing motif in the voltage sensing domain which is known to be crucial for proper gating (Bezanilla F. Nat. Rev. Mol. Cell Biol., 2008 Apr;9:323-32; Chamberlin A et al. J. Mol. Biol., 2015 Jan;427:131-45). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation for CACNA1A-related neurologic disorder; however, it is unlikely to be causative of CACNA1A-related spinocerebellar ataxia. |
| Labcorp Genetics |
RCV000653331 | SCV000775210 | pathogenic | Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 | 2025-03-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1664 of the CACNA1A protein (p.Arg1664Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset ataxia (PMID: 16325861, 28742085). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68432). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CACNA1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 28742085). For these reasons, this variant has been classified as Pathogenic. |
| Athena Diagnostics | RCV000406556 | SCV000612550 | likely pathogenic | not provided | 2017-06-16 | criteria provided, single submitter | clinical testing | |
| Centre for Mendelian Genomics, |
RCV000415457 | SCV000492918 | likely pathogenic | Global developmental delay; Enlarged cisterna magna | 2014-05-20 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000406556 | SCV000329829 | pathogenic | not provided | 2023-08-14 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect by significantly impairing the function of the protein (PMID: 28742085); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28742085, 16325861, 24486772, 32429945, 32637629, 37555011, 33349592, 34068417) |
| Solve- |
RCV003152591 | SCV005091512 | likely pathogenic | Developmental and epileptic encephalopathy, 42 | 2022-06-01 | no assertion criteria provided | provider interpretation | Variant confirmed as disease-causing by referring clinical team |
| Genome |
RCV000406556 | SCV002760025 | not provided | not provided | no classification provided | phenotyping only | Variant interpreted as Pathogenic and reported on 12-08-2021 by Lab or GTR ID 500031. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. | |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000406556 | SCV001968847 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Diagnostic Laboratory, |
RCV000406556 | SCV001963387 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Department of Rehabilitation Medicine, |
RCV000755049 | SCV000882749 | pathogenic | Ataxia _ Neurologic (child onset); Non-progressive congenital cerebellar ataxia | 2019-02-11 | no assertion criteria provided | research | |
| Baylor Genetics | RCV000679889 | SCV000807290 | uncertain significance | Episodic ataxia type 2 | 2017-09-01 | flagged submission | clinical testing | This mutation has been previously reported as disease-causing and was found four times in our laboratory as de novo findings in affected individuals. |
| Mendelics | RCV000157057 | SCV000199322 | pathogenic | Chronic and progressive ataxia | 2014-11-30 | no assertion criteria provided | clinical testing | |
| Uni |
RCV000059302 | SCV000090860 | not provided | Spinocerebellar ataxia type 6 | no classification provided | not provided |