ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial candidiasis 2 (MIM#212050). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity where age of onset and type of fungal infections can be variable. Penetrance is expected to be complete by the age of 52, however, it is incomplete in younger individuals (PMID: 30136218). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (563 heterozygotes, 2 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3) (3 heterozygotes, 0 homozygotes). (SB) 0508 - In silico predictions for abnormal splicing are uninformative. (I) 0705 - No comparable canonical splice site variants have previous evidence for pathogenicity. (I) 0806 - This variant has moderate previous evidence of being benign in unrelated individuals. This variant has previously been reported as likely benign (3x) and VUS (1x) in ClinVar. It has also been reported in a patient with primary immunodeficiency where one homozygous variant in each of the MYD88 and CARD9 genes was identified, and the patient's clinical phenotype was thought to be due to MYD88-deficiency (PMID: 30837984). Additionally, this variant was reported in a conference abstract in homozygous state in a child with recurrent fungal infection (PMID: 30809743). In the heterozygous state, this variant has been reported to confer strong effective effects against inflammatory bowel disease (PMID: 33414972). (SB) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

CARD9 NM_052813.4 exon 11 c.1434+1G>C: This variant has been reported in the heterozygous state in at least one individual with pulmonary nontuberculous mycobacterial infection (Szymanski 2015 PMID:26038974). This variant is also present in 0.7% (74/10266) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-139259592-C-G), including two homozygotes in the European population. Additionally, this variant has been reported in the literature to have a potentially protective effect for inflammatory bowel disease and Crohn's disease risk (Rivas 2011 PMID: 21983784, Beaudoin 2013 PMID:24068945). This variant is present in ClinVar (Variation ID:535816). Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. However, there is insufficient evidence to establish loss of function as a mechanism of disease for this gene at this time. In addition, this variant occurs towards the 3' end of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

CARD9: BS2