ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.4174G>T (p.Val1392Leu)

dbSNP: rs794727411
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center RCV001706925 SCV001934513 likely pathogenic Developmental and epileptic encephalopathy, 42 2020-09-09 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
Labcorp Genetics (formerly Invitae), Labcorp RCV003771862 SCV004591796 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2022-11-24 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1285568). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1393 of the CACNA1A protein (p.Val1393Leu). 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. 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. This variant disrupts the p.Val1393 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28007337, 29056246, 29100083, 30283815, 31468518). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

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