ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.4996C>T (p.Arg1666Trp)

dbSNP: rs121908220
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000059303 SCV000292240 pathogenic Migraine, familial hemiplegic, 1 2016-04-25 criteria provided, single submitter clinical testing Pathogenic variants in CACNA1A have been reported to cause familial hemiplegic migraine. Here we report a case of a female patient with hemiplegic migraine caused by a pathogenic variant in CACNA1A.
Athena Diagnostics RCV000991674 SCV001143331 likely pathogenic not provided 2019-08-12 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/278210 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Statistically associated with disease, but in a single family (p < 0.05).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000059303 SCV003930378 pathogenic Migraine, familial hemiplegic, 1 2023-06-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005222736 SCV005863225 pathogenic Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2024-07-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1667 of the CACNA1A protein (p.Arg1667Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hemiplegic migraine (PMID: 11439943). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68433). 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.Arg1667 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32170034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot RCV000059303 SCV000090861 not provided Migraine, familial hemiplegic, 1 no assertion provided not provided

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