Glanzmann thrombasthenia: genes and variants

Genes linked to Glanzmann thrombasthenia

• ITGA2B: Integrin alpha-IIb

  Together with ITGB3, it forms the major platelet fibrinogen receptor that becomes activated during platelet stimulation and drives aggregation. Biallelic loss-of-function variants cause Glanzmann thrombasthenia, a severe inherited platelet-aggregation disorder.

  74 disease-causing and 259 uncertain variants in ITGA2B are linked to Glanzmann thrombasthenia.

• ITGB3: Integrin beta-3

  In platelets it pairs with ITGA2B to bind fibrinogen and mediate aggregation, while in other cells it forms integrins involved in matrix adhesion and signaling. Biallelic loss-of-function variants cause Glanzmann thrombasthenia.

  61 disease-causing and 65 uncertain variants in ITGB3 are linked to Glanzmann thrombasthenia.

Where Glanzmann thrombasthenia variants cluster

• ITGB3 VWFA (positions 135–377): 34 of 61 disease-causing changes, 1.8× more than its size predicts.
• ITGA2B FG-GAP 3 (positions 187–238): 9 of 74 disease-causing changes, 2.4× more than its size predicts.
• ITGA2B FG-GAP 5 (positions 306–371): 9 of 74 disease-causing changes, 1.9× more than its size predicts.
• ITGB3 I-EGF 4 (positions 586–625): 6 of 61 disease-causing changes, 1.9× more than its size predicts.
• ITGA2B FG-GAP 4 (positions 251–305): 7 of 74 disease-causing changes, 1.8× more than its size predicts.

Known disease-causing variants in Glanzmann thrombasthenia

Showing 60 of 135.

Uncertain variants in Glanzmann thrombasthenia that look disease-causing

Which prediction tools work for Glanzmann thrombasthenia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 89 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 87 out of 100
• CATVariant: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 80 out of 100
• MetaLR: 78 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Diseases related to Glanzmann thrombasthenia

• Hypertrophic cardiomyopathy, also linked to ITGA2B and ITGB3
• Noonan syndrome, also linked to ITGA2B and ITGB3
• Costello syndrome, also linked to ITGA2B and ITGB3
• Myocardial infarction, also linked to ITGA2B and ITGB3
• Bleeding disorder, platelet-type, 24, also linked to ITGB3

Frequently asked questions

Which genes are linked to Glanzmann thrombasthenia?

In CATVariant, Glanzmann thrombasthenia is linked to 2 analyzed proteins: ITGA2B (Integrin alpha-IIb) and ITGB3 (Integrin beta-3).

How many genetic variants are linked to Glanzmann thrombasthenia?

569 variants: 135 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 324 are of uncertain significance or have conflicting reports.

Which uncertain variants in Glanzmann thrombasthenia look disease-causing?

4 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example ITGB3 C568Y, ITGA2B A341V, ITGA2B G296E and ITGA2B R358C. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Glanzmann thrombasthenia?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 74 disease-causing and 21 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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