Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000170799 | SCV000223354 | uncertain significance | not provided | 2013-07-26 | criteria provided, single submitter | clinical testing | p.Lys1211Glu (AAA>GAA): c.3631 A>G in exon 28 of the CACNA1C gene (NM_000719.6). The Lys1211Glu variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Lys1211Glu results in a non-conservative amino acid substitution of positively charged Lysine with a negatively charged Glutamic acid at a position that is conserved across species. In silico analysis predicts Lys1211Glu is damaging to the protein structure/function. The Lys1211Glu variant was not observed in approximately 6,500 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 residues have been reported in association with LQTS or Timothy syndrome. With the clinical and molecular information available at this time, we cannot definitively determine if Lys1211Glu is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). |
| Ambry Genetics | RCV003362707 | SCV004073022 | likely pathogenic | Cardiovascular phenotype | 2023-07-31 | criteria provided, single submitter | clinical testing | The p.K1211E variant (also known as c.3631A>G), located in coding exon 28 of the CACNA1C gene, results from an A to G substitution at nucleotide position 3631. The lysine at codon 1211 is replaced by glutamic acid, an amino acid with similar properties. This variant has been reported as occurring de novo in a case with long QT syndrome (LQTS) (Dufendach KA et al. JACC Clin Electrophysiol, 2018 Apr;4:459-466), and has been observed in an additional individual with a personal and/or family history consistent with LQTS (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of CACNA1C-related long QT syndrome/Timothy syndrome; however, its clinical significance for CACNA1C-related neurodevelopmental disorder is unclear. |