ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.1498A>G (p.Thr500Ala)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003785421 SCV004605036 likely pathogenic Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2024-01-14 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 501 of the CACNA1A protein (p.Thr501Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. 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 expected to disrupt CACNA1A protein function with a positive predictive value of 95%. This variant disrupts the p.Thr501 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20129625, 24498617, 34320921). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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