Submissions for variant NM_032415.7(CARD11):c.3145-3C>T

gnomAD frequency: 0.00077  dbSNP: rs200456391

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551661	SCV000653601	uncertain significance	Severe combined immunodeficiency due to CARD11 deficiency; BENTA disease	2024-01-29	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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200456391, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 473934). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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	Severe combined immunodeficiency due to CARD11 deficiency	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262448	SCV001440327	uncertain significance	BENTA disease	2019-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000788537	SCV001748196	uncertain significance	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821609	SCV002069874	likely benign	not specified	2021-06-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000788537	SCV004563881	likely benign	not provided	2023-11-07	criteria provided, single submitter	clinical testing