ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.6281C>T (p.Pro2094Leu)

gnomAD frequency: 0.00001  dbSNP: rs769128653
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000812748 SCV000953071 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2023-12-22 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2095 of the CACNA1A protein (p.Pro2095Leu). This variant is present in population databases (rs769128653, gnomAD 0.003%). 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: 656353). 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 with a positive predictive value of 95%. 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.
GeneDx RCV001585746 SCV001818003 uncertain significance not provided 2020-12-16 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002538130 SCV003692505 uncertain significance Inborn genetic diseases 2022-11-17 criteria provided, single submitter clinical testing The c.6284C>T (p.P2095L) alteration is located in exon 43 (coding exon 43) of the CACNA1A gene. This alteration results from a C to T substitution at nucleotide position 6284, causing the proline (P) at amino acid position 2095 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect - Brain Gene Registry RCV003444109 SCV004171209 not provided CACNA1A-related disorder no assertion provided phenotyping only Variant classified as Uncertain significance and reported on 05-20-2020 by GeneDx. 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 Dr. Philip Payne 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/.

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