ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect through a lack of expression of LFA-1 on the surface of cells expressing this variant (Hogg et al., 1999; Yamazaki-Nakashimada et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17651379, 30312521, 30968598, 34310689, 10936446, 25527966, 22134107, 25514840, 25703682, 30919141, 9884339, 31965297, 32279896, 33391282, 33365035, 33240318)

ITGB2 NM_000211.4 exon 7 p.Gly273Arg (c.817G>A): This variant has been reported in the literature in at least 3 individuals with Leukocyte Adhesion Deficiency Type-I (LAD-I) as homozygous or compound heterozygotes (Hogg 1999 PMID:9664339, Yamazaki-Nakashima 2015 PMID:25527966). This variant is present in 3/126630 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs137852618). This variant is present in ClinVar (Variation ID:9471). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies suggest a deleterious effect of this variant, potentially impacting the cell surface expression of Beta-2 integrins (Hogg 1999 PMID:9664339, Guan 2015 PMID:25514840, Yamazaki-Nakashima 2015 PMID:25527966). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ITGB2 function (PMID: 9884339). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITGB2 protein function. ClinVar contains an entry for this variant (Variation ID: 9471). This missense change has been observed in individual(s) with leukocyte adhesion deficiency type 1 (PMID: 9884339, 30919141; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs137852618, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 273 of the ITGB2 protein (p.Gly273Arg).