ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.5419G>T (p.Ala1807Ser)

dbSNP: rs1555736565
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626755 SCV000747458 likely pathogenic Global developmental delay; Strabismus; Generalized hypotonia 2017-01-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005213366 SCV005857024 likely pathogenic Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2024-04-10 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1808 of the CACNA1A protein (p.Ala1808Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CACNA1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 523409). 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.Ala1808 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 35217970; Invitae). 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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