Submissions for variant NM_020070.4(IGLL1):c.258del (p.Gln88fs)

dbSNP: rs532338576

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225003	SCV000676984	uncertain significance	Agammaglobulinemia 2, autosomal recessive	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln88Asnfs*7) in the IGLL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acid(s) of the IGLL1 protein. This variant is present in population databases (rs532338576, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Agammaglobulinemia, primary immunodeficiency, and/or reduced B lymphocytes and increased susceptibility to bacterial infection (PMID: 25502423, 32888943, 34619682). This variant is also known as c.[258_258del]. ClinVar contains an entry for this variant (Variation ID: 236015). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
3billion	RCV000225003	SCV002521879	pathogenic	Agammaglobulinemia 2, autosomal recessive	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.092%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with IGLL1 related disorder (ClinVar ID: VCV000236015 / PMID: 32888943). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000225003	SCV003924210	pathogenic	Agammaglobulinemia 2, autosomal recessive	2022-11-09	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in 4 individuals with features of a primary immunodeficency in the homozygous state (Mones 2014 PMID:25502423 {alt nomenclature-c.258delG,p.Gly86fs} Platt 2021 PMID:32888943, Sogkas 2021 PMID:34619682). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.1% [103/67812]; https://gnomad.broadinstitute.org/variant/22-23575030-AC-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 236015). Evolutionary conservation and computational prediction tools for this variant are limited or unavailable. This variant is a deletion of 1 nucleotide and creates a premature stop codon 7 amino acid positions downstream from this location, which is expected to result in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene however, evidence is still limited at this time. In summary, this variant is classified as pathogenic based on the data above.
OMIM	RCV000225003	SCV000281969	pathogenic	Agammaglobulinemia 2, autosomal recessive	2016-06-13	no assertion criteria provided	literature only
GenomeConnect - Brain Gene Registry	RCV000225003	SCV004012809	not provided	Agammaglobulinemia 2, autosomal recessive		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-14-2021 by Lab The Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.