ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.2623T>G (p.Ser875Ala) (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 Praxis fuer Humangenetik Tuebingen RCV000416083 SCV000493168 likely benign not provided 2016-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000416083 SCV000528273 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The S875A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 5,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S875A 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 RCV000543635 SCV000656726 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2017-05-23 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 875 of the CACNA1A protein (p.Ser875Ala). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and alanine. This variant is present in population databases (rs751675055, ExAC 0.003%) but has not been reported in the literature in individuals with a CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 374436). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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