ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.3046G>A (p.Gly1016Arg) (rs190551509)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000440429 SCV000534925 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The G1016R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G1016R variant is observed in 3/198 (1.5%) alleles from individuals of Kenyan background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G1016R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000706830 SCV000835903 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1016 of the CACNA1A protein (p.Gly1016Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 391779). 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: "Benign"; 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000440429 SCV001151712 likely benign not provided 2018-07-01 criteria provided, single submitter clinical testing

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