ClinVar Miner

Submissions for variant NM_032415.6(CARD11):c.3145-3C>T (rs200456391)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000551661 SCV000653601 uncertain significance Immunodeficiency 11; B-cell expansion with NFKB and T-cell anergy 2019-12-31 criteria provided, single submitter clinical testing This sequence change falls in intron 23 of the CARD11 gene. It does not directly change the encoded amino acid sequence of the CARD11 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs200456391, ExAC 0.1%). This variant has not been reported in the literature in individuals with CARD11-related disease. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Blueprint Genetics RCV000788537 SCV000927686 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853282 SCV000996116 likely pathogenic Immunodeficiency 11 2018-03-08 criteria provided, single submitter clinical testing This variant is predicted to affect the splice acceptor region of intron 23/24 at a highly conserved nucleotide. CARD11 is loss of function intolerant (pLI=1.00). However, there are no reports of this variant in the literature nor has it been previously reported as pathogenic. The variant is present in the gnomAD population databases at a very low frequency, with no reports of homozygotes, thus the variant is presumed to be rare. Based on the combined evidence, the variant is classified as likely pathogenic.

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