ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.1361G>A (p.Arg454Gln) (rs561858384)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658823 SCV000535295 uncertain significance not provided 2018-06-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The R455Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R455Q 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). The R455Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Athena Diagnostics Inc RCV000420690 SCV000612506 uncertain significance not specified 2016-09-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000658823 SCV000701760 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658823 SCV000780619 likely pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000715680 SCV000846511 uncertain significance History of neurodevelopmental disorder 2016-05-17 criteria provided, single submitter clinical testing The p.R455Q variant (also known as c.1364G>A), located in coding exon 11 of the CACNA1A gene, results from a G to A substitution at nucleotide position 1364. The arginine at codon 455 is replaced by glutamine, an amino acid with highly 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 6014 samples (12028 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Based on available evidence to date, the clinical significance of this variant remains unclear.
Invitae RCV000795075 SCV000934516 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 455 of the CACNA1A protein (p.Arg455Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs561858384, ExAC 0.005%). This variant has been observed in an individual affected with episodic ataxia type 2 (PMID: 28540055). ClinVar contains an entry for this variant (Variation ID: 392083). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.

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