ClinVar Miner

Submissions for variant NM_000211.5(ITGB2):c.1777C>T (p.Arg593Cys)

gnomAD frequency: 0.00001  dbSNP: rs137852609
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000799618 SCV000939289 pathogenic Leukocyte adhesion deficiency 1 2023-06-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ITGB2 function (PMID: 1968911, 11703376). 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: 9458). This missense change has been observed in individual(s) with leukocyte adhesion deficiency (PMID: 1968911, 7705401, 11703376, 12488604, 25703682). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs137852609, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 593 of the ITGB2 protein (p.Arg593Cys).
3billion, Medical Genetics RCV000799618 SCV002521348 pathogenic Leukocyte adhesion deficiency 1 2022-05-22 criteria provided, single submitter clinical testing The variant has been previously observed in at least two affected individuals with a consistent phenotype from unrelated families (PMID: 25703682, 11703376). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.857>=0.6). It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Amino acid change identical to known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000009458, PMID:1968911). (PS1_S). The same variant was previously reported in trans with another pathogenic variant in this gene at least 2 times (PMID: 1968911, 7705401). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences RCV003407313 SCV004108784 pathogenic ITGB2-related disorder 2023-04-24 criteria provided, single submitter clinical testing The ITGB2 c.1777C>T variant is predicted to result in the amino acid substitution p.Arg593Cys. This variant has been previously reported in the homozygous or compound heterozygous state in individuals with leukocyte adhesion deficiency (Arnaout et al. 1990. PubMed ID: 1968911; Wright et al. 1995. PubMed ID: 7705401; Fathallah et al. 2001. PubMed ID: 12488604; patient TB in Shaw et al. 2001. PubMed ID: 11703376; P16 in Madkaikar et al. 2015. PubMed ID: 25703682; Yaz et al. 2021. PubMed ID: 34310689). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-46309291-G-A). This variant is interpreted as pathogenic.
GeneDx RCV004794327 SCV005414731 pathogenic not provided 2024-05-24 criteria provided, single submitter clinical testing Published functional studies demonstrate reduced expression of CD11b/CD18 heterodimers supporting a deleterious effect on protein function (PMID: 1968911); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34310689, 25514840, 33391282, 11703376, 25703682, 33365035, 1968911, 12488604, 29750748, 37601427, 22134107, 36696755, 7705401)
OMIM RCV000799618 SCV000030287 pathogenic Leukocyte adhesion deficiency 1 1990-03-01 no assertion criteria provided literature only

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