ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.2407C>A (p.Arg803Ser) (rs760816963)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720462 SCV000851339 uncertain significance History of neurodevelopmental disorder 2016-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000481834 SCV000572807 uncertain significance not provided 2017-01-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The R803S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R803S variant is observed in 6/66518 (0.009%) alleles from individuals of non-Finnish European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R803S 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 in mammals, and a missense variant in a nearby residue (M798T) has been reported in the Human Gene Mutation Database in association with a CACNA1A-related disorder (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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 RCV000703860 SCV000832784 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2018-05-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 803 of the CACNA1A protein (p.Arg803Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs760816963, ExAC 0.009%). This variant has been observed in a family with symptoms of episodic ataxia 2 (PMID: 28455667). ClinVar contains an entry for this variant (Variation ID: 423150). 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.

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