ClinVar Miner

Submissions for variant NM_032415.6(CARD11):c.224G>A (p.Arg75Gln) (rs1064795280)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726904 SCV000704024 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001176 SCV001158328 likely pathogenic none 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.

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