ClinVar Miner

Submissions for variant NM_032415.7(CARD11):c.704G>A (p.Arg235Gln)

gnomAD frequency: 0.00004  dbSNP: rs148083162
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001322693 SCV001513578 uncertain significance Severe combined immunodeficiency due to CARD11 deficiency; BENTA disease 2023-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 235 of the CARD11 protein (p.Arg235Gln). This variant is present in population databases (rs148083162, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with CARD11-related conditions. ClinVar contains an entry for this variant (Variation ID: 1022746). 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. 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.
Genetic Services Laboratory, University of Chicago RCV001820014 SCV002065744 uncertain significance not specified 2021-11-22 criteria provided, single submitter clinical testing DNA sequence analysis of the CARD11 gene demonstrated a sequence change, c.704G>A, in exon 6 that results in an amino acid change, p.Arg235Gln. This sequence change has been described in the gnomAD database with a frequency of 0.011% in the Latino/admixed American subpopulation (dbSNP rs148083162). The p.Arg235Gln change affects a moderately conserved amino acid residue located in a domain of the CARD11 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg235Gln substitution. This sequence change does not appear to have been previously described in individuals with CARD11-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg235Gln change remains unknown at this time.
PreventionGenetics, part of Exact Sciences RCV003416207 SCV004113267 uncertain significance CARD11-related disorder 2022-12-20 criteria provided, single submitter clinical testing The CARD11 c.704G>A variant is predicted to result in the amino acid substitution p.Arg235Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-2979543-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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