Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Blueprint Genetics | RCV000208397 | SCV000263824 | uncertain significance | Primary familial hypertrophic cardiomyopathy | 2014-12-16 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000560482 | SCV000654835 | uncertain significance | Arrhythmogenic right ventricular dysplasia 13 | 2023-04-11 | 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 CTNNA3 protein function. ClinVar contains an entry for this variant (Variation ID: 222538). This variant has not been reported in the literature in individuals affected with CTNNA3-related conditions. This variant is present in population databases (rs751471841, gnomAD 0.005%). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 358 of the CTNNA3 protein (p.Thr358Asn). |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786291 | SCV000925052 | uncertain significance | not provided | 2017-07-24 | no assertion criteria provided | provider interpretation | p.Thr358Asn (T358N; c.1073C>A) in exon 8 of the CTNNA3 gene (NM_013266.3) Chromosome position 10:68535257 G / T Based on the information reviewed below, 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 variant has not previously been reported in association with disease. The CTNNA3 gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC)—which is not our patient’s phenotype. Our patient does have another Likely Pathogenic variant that explains his phenotype (familial sick sinus syndrome). This is a conservative amino acid change, resulting in the replacement of a polar threonine with a polar asparagine. Threonine at this location is poorly conserved across ~100 vertebrate species for which we have data, and is frequently a nonpolar alanine instead (sometimes a proline, or valine). As of as of 7/24/2017, there are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side. According to the Invitae report, Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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. Overall MAF of 0.003%. Specifically, the variant was observed in 6 individuals with non-Finnish European ancestry (for the highest allele frequency: 0.005%), and 1 individual with African ancestry. 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. |