Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000473490 | SCV000553015 | uncertain significance | Long QT syndrome | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1226 of the CACNA1C protein (p.Phe1226Leu). This variant is present in population databases (rs775309900, gnomAD 0.0009%). 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: 411725). 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 not expected to disrupt CACNA1C protein function with a negative predictive value of 80%. 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. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786280 | SCV000925037 | uncertain significance | not provided | 2017-04-08 | no assertion criteria provided | provider interpretation | Our patient is a 14 year-old with paroxysmal atrial fibrillation. He was tested at Invitae. p.Phe1226Leu (c.3678C>G) in exon 28 of the CACNA1C gene (NM_000719.6; ENST00000399655.5) Chromosome position 12:2719826 C / G We classify this as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This is a rare variant that has not been reported in the literature in association with disease. It is present in just one individual in population databases (gnomAD). The CACNA1C gene is associated with autosomal dominant Timothy syndrome (TS), also known as long QT syndrome (LQTS) type 8 (MedGen UID: 331395), Brugada syndrome (BrS) (MedGen UID: 395633), and short QT syndrome (SQTS) (MedGen UID: 378835). This is a conservative amino acid change, resulting in the replacement of a nonpolar phenylalanine with a nonpolar leucine. Phenylalanine at this location is absolutely conserved across all ~100 vertebrate species for which we have data. No missense variation at nearby residues (+/- 10) is listed in ClinVar as Likely Pathogenic or Pathogenic as of 4/8/2017. According to the Invitae report, in silico analysis programs do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In total the variant has been seen in 1 out of 123,132 individuals from publicly available population datasets. Specifically, it was reported in 1/55,856 non-Finnish European ancestry individuals whose exomes are in the gnomAD database. There is no other reported missense variation at this codon. gnomAD includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Our patient’s ancestry is Northern European Caucasian. There is good sequencing coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. |