Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000170794 | SCV000223349 | uncertain significance | not provided | 2018-01-24 | criteria provided, single submitter | clinical testing | p.Arg895His (CGC>CAC): c.2684 G>A in exon 20 of the CACNA1C gene (NM_000719.6). The Arg895His variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg895His results in a conservative amino acid substitution of of one positively charged amino acid with another at a position that is conserved across species. In silico analysis predicts Arg895His is probably damaging to the protein structure/function. The Arg895His variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with LQTS, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Arg895His is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). |
Invitae | RCV000465144 | SCV000553014 | uncertain significance | Long QT syndrome | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 895 of the CACNA1C protein (p.Arg895His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 190656). 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 CACNA1C 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. |
Department of Genetics, |
RCV003126565 | SCV003804117 | likely benign | Autism spectrum disorder | 2021-08-13 | criteria provided, single submitter | clinical testing |