rs137852907
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3_SupportingPP3PM2_SupportingPS3_ModeratePP4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.818G>A (p.Gly273Asp) variant has been reported, in the homozygous state (PM3_supporting), in at least one proband (PMID:8282784) with a GT-specific phenotype. The patient in PMID:8282784 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, the patient had <5% expression by flow cytometry. The variant is absent from gnomADv4.0 (PM2_supporting) and is predicted deleterious (REVEL score 0.845; PP3). Heterologous expression followed by the preferred assays, of either Western blot or flow cytometry, has not been reported for this variant. However in PMID:8282784, to test for mutant complexes on the cell surface, COS-1 cells were cotransfected with WT ITGB3 and Gly273Asp ITGA2B, cells were surface labeled with 125I and immunoprecipitated, then labeled heterodimers were detected on the surface of cotransfected cells containing wildtype ITGA2B but not on the surface of cells containing Gly273Asp. PMID:8916916 reports similar immunoprecipitation results. These results were considered sufficient evidence of impaired surface expression for application of the PS3_moderate criteria. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3_moderate, PM2_supporting, PM3_supporting, PP3, and PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115837/MONDO:0010119/011
Frequency
Consequence
NM_000419.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ITGA2B | NM_000419.5 | c.818G>A | p.Gly273Asp | missense_variant | 8/30 | ENST00000262407.6 | NP_000410.2 | |
ITGA2B | XM_011524749.2 | c.971G>A | p.Gly324Asp | missense_variant | 8/29 | XP_011523051.2 | ||
ITGA2B | XM_011524750.2 | c.971G>A | p.Gly324Asp | missense_variant | 8/29 | XP_011523052.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ITGA2B | ENST00000262407.6 | c.818G>A | p.Gly273Asp | missense_variant | 8/30 | 1 | NM_000419.5 | ENSP00000262407.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Glanzmann thrombasthenia Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | May 02, 2024 | The NM_000419.5(ITGA2B):c.818G>A (p.Gly273Asp) variant has been reported, in the homozygous state (PM3_supporting), in at least one proband (PMID: 8282784) with a GT-specific phenotype. The patient in PMID: 8282784 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, the patient had <5% expression by flow cytometry. The variant is absent from gnomADv4.0 (PM2_supporting) and is predicted deleterious (REVEL score 0.845; PP3). Heterologous expression followed by the preferred assays, of either Western blot or flow cytometry, has not been reported for this variant. However in PMID: 8282784, to test for mutant complexes on the cell surface, COS-1 cells were cotransfected with WT ITGB3 and Gly273Asp ITGA2B, cells were surface labeled with 125I and immunoprecipitated, then labeled heterodimers were detected on the surface of cotransfected cells containing wildtype ITGA2B but not on the surface of cells containing Gly273Asp. PMID: 8916916 reports similar immunoprecipitation results. These results were considered sufficient evidence of impaired surface expression for application of the PS3_moderate criteria. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3_moderate, PM2_supporting, PM3_supporting, PP3, and PP4_moderate. - |
Glanzmann thrombasthenia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1994 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at