Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000756272 | SCV000884031 | likely pathogenic | not provided | 2018-04-01 | criteria provided, single submitter | clinical testing | The IGLL1 c.425C>T; p.Pro142Leu variant (rs1064422, ClinVar variant ID 14825) has been found in two patients with agammaglobulinemia and severely reduced B cell levels; one patient was a compound heterozygote, with a premature stop codon on the other chromosome (Minegishi 1998), and the other was a homozygote (Gemayel 2016). Both patients’ IGLL1 genes contained several variants that match the sequence of the highly homologous pseudogene IGLL3P, suggesting the possibility of gene conversion events. Functional studies found that the mutant protein appeared to fold incorrectly and it was not secreted by transfected cells (Minegishi 1998). This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.07% (identified on 85 out of 126,310 chromosomes). The proline at position 142 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Pro142Leu variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the p.Pro142Leu variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000015949 | SCV000936305 | uncertain significance | Agammaglobulinemia 2, autosomal recessive | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 142 of the IGLL1 protein (p.Pro142Leu). This variant is present in population databases (rs1064422, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with B-cell deficiency and hypogammaglobulinemia (PMID: 9419212). ClinVar contains an entry for this variant (Variation ID: 14825). 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. 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. |
| Genomic Research Center, |
RCV001170010 | SCV001251930 | uncertain significance | not specified | 2020-05-03 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000756272 | SCV004152272 | likely benign | not provided | 2023-10-01 | criteria provided, single submitter | clinical testing | IGLL1: BP4 |
| OMIM | RCV000015949 | SCV000036216 | pathogenic | Agammaglobulinemia 2, autosomal recessive | 1998-01-05 | no assertion criteria provided | literature only | |
| Prevention |
RCV004758593 | SCV005345454 | uncertain significance | IGLL1-related condition | 2024-09-11 | no assertion criteria provided | clinical testing | The IGLL1 c.425C>T variant is predicted to result in the amino acid substitution p.Pro142Leu. This variant was reported in two individuals with primary immunodeficiency, one of which was homozygous, and the other of which had a nonsense variant in trans (Giżewska et al. 2020. PubMed ID: 33178177; Minegishi et al. 1998. PubMed ID: 9419212). This variant is reported in 0.071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, this variant has been reported in cis along with c.393T>C and c.420T>C, which correspond to reference sequence in the pseudogene and indicates a potential conversion event at this locus (Minegishi et al. 1998. PubMed ID: 9419212). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |