ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.3764T>C (p.Met1255Thr)

dbSNP: rs1085307644
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489907 SCV000576925 uncertain significance not provided 2017-04-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The M1256T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M1256T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M1256T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV002523412 SCV003010483 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1256 of the CACNA1A protein (p.Met1256Thr). This variant is not present in population databases (gnomAD no frequency). 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: 426475). 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%. 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.

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