Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000726904 | SCV000570945 | uncertain significance | not provided | 2016-07-07 | criteria provided, single submitter | clinical testing | The R75Q variant in the CARD11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R75Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R75Q as a variant of uncertain significance. |
| Eurofins Ntd Llc |
RCV000726904 | SCV000704024 | uncertain significance | not provided | 2016-11-28 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000726904 | SCV001158328 | likely pathogenic | not provided | 2019-08-01 | criteria provided, single submitter | clinical testing | The CARD11 c.224G>A; p.Arg75Gln variant (rs1064795280) is reported in the literature in an individual with symptoms of immunodeficiency (Dorjbal 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, but it is reported in ClinVar (Variation ID: 421663). The arginine at codon 75 is highly conserved, it occurs in the functionally important CARD domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with these predictions, cultured cells expressing the p.Arg75Gln exhibit defects in NF-KB and mTORC signaling, and co-transfection of p.Arg75Gln with wildtype CARD11 suggests the variant protein exerts a dominant negative effect on cellular NF-KB signaling (Dorjbal 2019). Based on available information, this variant is considered to be likely pathogenic. References: Dorjbal B et al. Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease. J Allergy Clin Immunol. 2019 Apr;143(4):1482-1495. |
| Labcorp Genetics |
RCV002526603 | SCV003472498 | uncertain significance | Severe combined immunodeficiency due to CARD11 deficiency; BENTA disease | 2023-09-06 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with clinical features of CARD11-related conditions (PMID: 30170123). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CARD11 function (PMID: 30170123). 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 CARD11 protein function. ClinVar contains an entry for this variant (Variation ID: 421663). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 75 of the CARD11 protein (p.Arg75Gln). |