Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Immunogenetics Laboratory, |
RCV000663342 | SCV000778463 | likely pathogenic | Pancytopenia due to IKZF1 mutations | 2018-06-11 | criteria provided, single submitter | clinical testing | This is a novel low frequency variant (0.00082%). The nucleotide is highly conserved and the amino acid is moderately conserved. Prediction programs SIFT predicted deleterious (score: 0.03, median: 4.32), Mutation taster predicted disease causing (p-value: 1), and PolyPhen-2 predicted probably damaging (score 1.000). Germline IKZF1 mutations have been identified recently as a cause of common variable immunodeficiency and dysgammaglobulinemia through IKAROS haploinsufficiency (Bogaert 2018). They are autosomal dominantly inherited. This patient has the characteristics of IKZF1 deficiency, such as autoimmune disease, frequent infections, hematopoietic abnormality, and dysgammaglobinemia. No mutations are identified in other known CVID genes and 250 primary immunodeficiency genes in this patient. It is very likely that this variant is the cause of the patient’s disease. |
Gene |
RCV001584525 | SCV001814107 | uncertain significance | not provided | 2019-08-29 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
Invitae | RCV001584525 | SCV004387286 | uncertain significance | not provided | 2023-09-20 | criteria provided, single submitter | clinical testing | This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 22 of the IKZF1 protein (p.Asp22Asn). This variant has not been reported in the literature in individuals affected with IKZF1-related conditions. 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 548932). |