ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.2620T>G (p.Ser874Ala)

gnomAD frequency: 0.00001  dbSNP: rs751675055
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000416083 SCV000493168 uncertain significance not provided 2023-07-01 criteria provided, single submitter clinical testing CACNA1A: PP2, PP3
GeneDx RCV000416083 SCV000528273 uncertain significance not provided 2021-07-01 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Invitae RCV000543635 SCV000656726 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2023-12-01 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 875 of the CACNA1A protein (p.Ser875Ala). This variant is present in population databases (rs751675055, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 374436). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1A protein function with a negative predictive value of 95%. 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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