Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001342802 | SCV001536749 | uncertain significance | Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2216 of the CACNA1A protein (p.His2216Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of CACNA1A-related conditions (Invitae). This missense change has been observed in at least one individual who was not affected with CACNA1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 1039348). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1A protein function. 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 |
RCV001566724 | SCV001790286 | uncertain significance | not provided | 2023-07-07 | criteria provided, single submitter | clinical testing | Observed in patient with small vessel disease in published literature (Tan et al., 2019); however, no further clinical information was provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28539123, 31719132) |
| Fulgent Genetics, |
RCV002493757 | SCV002782675 | uncertain significance | Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42 | 2022-04-06 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004699319 | SCV005203068 | uncertain significance | not specified | 2024-07-09 | criteria provided, single submitter | clinical testing | Variant summary: CACNA1A c.6647A>C (p.His2216Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-06 in 13779922 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CACNA1A causing Epileptic Encephalopathy, Early Infantile, 42, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.6647A>C in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1039348). Based on the evidence outlined above, the variant was classified as uncertain significance. |