ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.1364G>A (p.Arg455Gln) (rs561858384)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000715680 SCV000846511 uncertain significance History of neurodevelopmental disorder 2016-05-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Athena Diagnostics Inc RCV000420690 SCV000612506 uncertain significance not specified 2016-09-26 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658823 SCV000780619 likely pathogenic not provided 2018-03-31 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
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.
Invitae RCV000795075 SCV000934516 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2018-12-12 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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