Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003771666 | SCV004585859 | pathogenic | Severe combined immunodeficiency due to CARD11 deficiency; BENTA disease | 2023-09-18 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 33202260). Experimental studies have shown that disruption of this splice site affects CARD11 function (PMID: 33202260). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1184835). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal dominant immunodeficiency 11B with atopic dermatitis (PMID: 33202260; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the CARD11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CARD11 are known to be pathogenic (PMID: 23374270, 23561803, 26289640). |
| Ambry Genetics | RCV004611847 | SCV005102717 | uncertain significance | Inborn genetic diseases | 2024-05-09 | criteria provided, single submitter | clinical testing | The c.358+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the CARD11 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In one functional study, this variant showed a moderate dominant negative impact (Meitlis, 2020). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| University of Washington Center for Mendelian Genomics, |
RCV001543393 | SCV001761951 | likely pathogenic | Immunodeficiency 11b with atopic dermatitis | no assertion criteria provided | research |