ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.4978C>T (p.Arg1660Cys)

gnomAD frequency: 0.00001  dbSNP: rs779576853
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001763278 SCV001990676 likely pathogenic not provided 2022-12-02 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV002034491 SCV002279667 likely pathogenic Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2024-03-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1661 of the CACNA1A protein (p.Arg1661Cys). This variant is present in population databases (rs779576853, gnomAD 0.003%). 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: 1308366). 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.Arg1661 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10987655, 29482223). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV004584441 SCV005073680 likely pathogenic Developmental and epileptic encephalopathy, 42 2024-07-05 criteria provided, single submitter clinical testing

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