ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.6549G>A (p.Met2183Ile)

gnomAD frequency: 0.00001  dbSNP: rs1335828021
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001223876 SCV001396044 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2184 of the CACNA1A protein (p.Met2184Ile). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 951877). 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 not expected to disrupt CACNA1A protein function with a negative predictive value of 95%. 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.
GeneDx RCV002256709 SCV002526606 uncertain significance not provided 2022-06-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002563046 SCV003553615 uncertain significance Inborn genetic diseases 2022-02-10 criteria provided, single submitter clinical testing The c.6552G>A (p.M2184I) alteration is located in exon 46 (coding exon 46) of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 6552, causing the methionine (M) at amino acid position 2184 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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