ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.6070G>A (p.Gly2024Ser) (rs574805525)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000421580 SCV000528580 uncertain significance not provided 2016-06-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The G2024S variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observedin approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome SequencingProject and was not observed with any significant frequency in the 1000 Genomes Project. The G2024S variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differin polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved.In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the proteinstructure/function. Therefore, based on the currently available information, it is unclear whether this variant is apathogenic variant or a rare benign variant.
Invitae RCV000653329 SCV000775208 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2024 of the CACNA1A protein (p.Gly2024Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs574805525, ExAC 0.2%). This variant has not been reported in the literature in individuals with CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 386799). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Athena Diagnostics Inc RCV000421580 SCV001143341 likely benign not provided 2019-05-21 criteria provided, single submitter clinical testing

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