ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.6530G>T (p.Gly2177Val) (rs763045560)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486833 SCV000574274 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The c.6530 G>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.6530 G>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.6530 G>T may damage or destroy the natural splice acceptor site for intron 45 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.6530 G>T variant does not inpact splicing, it will result in the G2177V missense variant. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the G2177V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000545131 SCV000656792 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 2177 of the CACNA1A protein (p.Gly2177Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs763045560, ExAC no frequency) but has not been reported in the literature in individuals with a CACNA1A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000719672 SCV000850542 uncertain significance History of neurodevelopmental disorder 2017-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.