Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000489287 | SCV000577444 | pathogenic | not provided | 2017-10-23 | criteria provided, single submitter | clinical testing | The V176M variant in the CACNA1A gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V176M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V176M variant has been identified as a de novo variant in two individuals previously tested at GeneDx. This substitution occurs at a position that is conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The V176M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The V176M variant is considered a pathogenic variant. |
| Ce |
RCV000489287 | SCV001249842 | uncertain significance | not provided | 2019-10-01 | criteria provided, single submitter | clinical testing | |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV003313959 | SCV004013268 | likely pathogenic | CACNA1A-related disorder | 2023-06-05 | criteria provided, single submitter | clinical testing | PS2, PS4_Supporting, PM2, PP2, PP3 |
| Labcorp Genetics |
RCV005213303 | SCV005858028 | uncertain significance | Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 | 2024-07-06 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 176 of the CACNA1A protein (p.Val176Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 29455050, 33057194). ClinVar contains an entry for this variant (Variation ID: 426878). 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. |