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.
ClinVar Genomic variation as it relates to human health
NM_000211.5(ITGB2):c.1777C>T (p.Arg593Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(4)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000211.5(ITGB2):c.1777C>T (p.Arg593Cys)
Variation ID: 9458 Accession: VCV000009458.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 44889376 (GRCh38) [ NCBI UCSC ] 21: 46309291 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 14, 2024 Jun 9, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000211.5:c.1777C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000202.3:p.Arg593Cys missense NM_001127491.3:c.1777C>T NP_001120963.2:p.Arg593Cys missense NM_001303238.2:c.1570C>T NP_001290167.1:p.Arg524Cys missense NC_000021.9:g.44889376G>A NC_000021.8:g.46309291G>A NG_007270.2:g.44463C>T LRG_76:g.44463C>T LRG_76t1:c.1777C>T LRG_76p1:p.Arg593Cys - Protein change
- R593C, R524C
- Other names
- -
- Canonical SPDI
- NC_000021.9:44889375:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| ITGB2 | - | - |
GRCh38 GRCh37 |
794 | 901 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 9, 2023 | RCV000799618.11 | |
|
ITGB2-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 24, 2023 | RCV003407313.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Leukocyte adhesion deficiency 1
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521348.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Recurrent skin infections (present) , Immunodeficiency (present) , Leukocytosis (present)
|
|
|
Pathogenic
(Apr 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
ITGB2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004108784.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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. (less)
|
|
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Pathogenic
(Jun 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Leukocyte adhesion deficiency 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000939289.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 9458). For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or … (more)
ClinVar contains an entry for this variant (Variation ID: 9458). 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. 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). (less)
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|
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Pathogenic
(Mar 01, 1990)
|
no assertion criteria provided
Method: literature only
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LEUKOCYTE ADHESION DEFICIENCY 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030287.3
First in ClinVar: Apr 04, 2013 Last updated: May 10, 2021 |
Comment on evidence:
Arnaout et al. (1990) found that a patient with leukocyte adhesion deficiency (LAD1; 116920) was compound heterozygous for 2 mutations in the CD18 gene: arg593-to-cys … (more)
Arnaout et al. (1990) found that a patient with leukocyte adhesion deficiency (LAD1; 116920) was compound heterozygous for 2 mutations in the CD18 gene: arg593-to-cys and lys196-to-thr. These amino acids lie in regions necessary for normal cell surface expression of CD18 and possibly other integrin-beta subunits. Arnaout et al. (1990) demonstrated that each mutant allele resulted in impaired CD18 expression on the cell surface membrane of transfected COS M6 cells. (less)
|
Comment:
Comment:
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.
Comment:
ClinVar contains an entry for this variant (Variation ID: 9458). 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. 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).
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
ClinVar contains an entry for this variant (Variation ID: 9458). 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. 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).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular characterization of leukocyte adhesion deficiency-I in Indian patients: identification of 9 novel mutations. | Madkaikar M | Blood cells, molecules & diseases | 2015 | PMID: 25703682 |
| Two Novel Frame Shift, Recurrent and De Novo Mutations in the ITGB2 (CD18) Gene Causing Leukocyte Adhesion Deficiency in a Highly Inbred North African Population. | Fathallah DM | Journal of biomedicine & biotechnology | 2001 | PMID: 12488604 |
| Characterization of four CD18 mutants in leucocyte adhesion deficient (LAD) patients with differential capacities to support expression and function of the CD11/CD18 integrins LFA-1, Mac-1 and p150,95. | Shaw JM | Clinical and experimental immunology | 2001 | PMID: 11703376 |
| Molecular characterization of leukocyte adhesion deficiency in six patients. | Wright AH | European journal of immunology | 1995 | PMID: 7705401 |
| Point mutations impairing cell surface expression of the common beta subunit (CD18) in a patient with leukocyte adhesion molecule (Leu-CAM) deficiency. | Arnaout MA | The Journal of clinical investigation | 1990 | PMID: 1968911 |
Text-mined citations for rs137852609 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.