Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000991676 | SCV001143334 | uncertain significance | not provided | 2019-07-16 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001858738 | SCV002156754 | uncertain significance | Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 | 2022-07-25 | criteria provided, single submitter | clinical testing | This sequence change affects codon 1751 of the CACNA1A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CACNA1A protein. This variant also falls at the last nucleotide of exon 34, which is part of the consensus splice site for this exon. This variant is present in population databases (rs781588570, gnomAD 0.0009%). This variant has been observed in individual(s) with clinical features of CACNA1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 804609). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg1751 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been observed in individuals with CACNA1A-related conditions (PMID: 19864665, 31288946), which suggests that this may be a clinically significant amino acid residue. 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. |
| Gene |
RCV000991676 | SCV003924694 | uncertain significance | not provided | 2023-05-12 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; In addition, in silico predictors and evolutionary conservation suggest the missense change may have a deleterious effect on the protein; In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site but the effect on protein function is unclear |