Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV000192693 | SCV002768980 | likely pathogenic | Immunodeficiency, common variable, 12 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with common variable immunodeficiency 12 (MIM# 616576). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance is estimated to be 60%, with some carriers appearing asymptomatic (PMID: 29477724). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been shown to result in an in-frame deletion of exon 8 (p.(Asp191_Lys244delinsGlu)). Both EBV cell lines transformed with patient lymphocytes and HEK293T cells transfected with the mutant construct demonstrated weak expression of the precursor mutant protein (p105delEx8) and none of the processed p50delEx8, suggesting that the mutant protein is degraded and resulting in p50 haploinsufficiency (PMID: 26279205). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable non-canonical splice variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported as pathogenic in LOVD with no supporting information. In addition, this variant has been shown to segregate in at least ten affected individuals within the family of this proband; however five individuals presenting with hypogammaglobulinaemia did not have this variant (PMID: 26279205). Lastly, a substitution on the adjacent nucleotide, c.730+5G>A, resulting in the same protein consequence as our variant, c.730+4A>G, has recently been reported in one individual with pyoderma gangrenosum (PMID: 34447408). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| OMIM | RCV000192693 | SCV000246276 | pathogenic | Immunodeficiency, common variable, 12 | 2015-09-03 | no assertion criteria provided | literature only |