Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000646201 | SCV000767960 | uncertain significance | Brugada syndrome 4 | 2023-05-31 | criteria provided, single submitter | clinical testing | 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. 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 CACNB2 protein function. ClinVar contains an entry for this variant (Variation ID: 537368). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This variant is present in population databases (rs774654438, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 493 of the CACNB2 protein (p.Arg493Cys). |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786282 | SCV000925040 | uncertain significance | not provided | 2017-09-28 | no assertion criteria provided | provider interpretation | Found in a 14 yo female with incomplete RBBB and two episodes of unexplained syncope during exercise. Her echocardiogram and cardiac MRI were read as normal. p.Arg493Cys (c.1477C>T) in exon 13 of the CACNB2 gene (NM_201590.2; ENST00000377329.8) Chromosome location 10:18828309 C / T Based on the information reviewed below, we classify this as a Variant of Unknown Significance, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. It is present, however, in population databases. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine capable of forming disulfide bridges. Arginine at this location is well conserved across ~100 vertebrate species for which we have data, although in a few species it is a positively-charge Lysine. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. However, a Ser481Leu variant was submitted to ClinVar by GeneReviews as Pathogenic; it segregated with disease in 6 affected family members with ST-Segment elevation, shorter-than-normal QTc intervals (less than 360 msec for males and 370 msec for females), syncope, and SCD, and patch clamp studies in vitro showed a loss of function in calcium channel activity (Antzelevitch et al. 2007). According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").. This variant was reported in 7 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 6 out of 55,792 non-Finnish Europeans (for minor allele frequency: 0.005%), and 1 East Asian. gnomAD also contains 25 individuals with another amino acid change at this site: p.Arg493His (maintaining the positive charge), and 1 with p.Arg493Ser. 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. |