Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000212.2(ITGB3):c.2332T>C (p.Ser778Pro)

CA123230

13556 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 889d0d53-4ad6-4a68-8d3e-86cda55b07ac

HGVS expressions

NM_000212.2:c.2332T>C

NM_000212.2(ITGB3):c.2332T>C (p.Ser778Pro)

NC_000017.11:g.47310169T>C

CM000679.2:g.47310169T>C

NC_000017.10:g.45387535T>C

CM000679.1:g.45387535T>C

NC_000017.9:g.42742534T>C

NG_008332.2:g.61328T>C

ENST00000559488.7:c.2332T>C

ENST00000559488.5:c.2332T>C

ENST00000560629.1:n.2266+2532T>C

NR_110880.1:n.363-6387A>G

NR_110881.1:n.227-6387A>G

NM_000212.3:c.2332T>C

NM_000212.3(ITGB3):c.2332T>C (p.Ser778Pro)

Uncertain Significance

PS3 PM2_Supporting

PP4 PP3 PM3

Evidence Links 1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.2(ITGB3):c.2332T>C (p.Ser778Pro) missense variant has been reported in at one Glanzmann thrombasthenia patient (PMID: 1438206). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The receptor function of αIIbβ3, measured by functional flow cytometry, in CHO cells transiently co-transfected with the Ser778Pro variant β3 and wild type αIIb showed minimal binding to ligand mimetic antibody PAC-1 indicating that this variant impacts protein function (PMID: 8080992; PS3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PM2_supporitng. (VCEP specifications version 2; date of approval 11/04/2021).

PS3

The receptor function of αIIbβ3, measured by functional flow cytometry, in CHO cells transiently co-transfected with the Ser778Pro variant β3 and wild type αIIb showed minimal binding to ligand mimetic antibody PAC-1 indicating that this variant impacts protein function (PMID: 8080992; PS3). Similar results were also reported in PMID: 7721884 and PMID: 12199799 found this variant specifically lacked high-affinity fibrinogen binding.

Ser778Pro was introduced into β3 and cotransfected into CHO cells with a chimeric α subunit consisting of the αIIb extracellular and transmembrane domains and the α6B cytoplasmic domain. The substitution of the αIIb cytoplasmic domain with that of α6 led to activation of αIIbβ3 to bind PAC1 (measured by flow cytometry), mimicking inside-out signaling. This effect was reversed by the Ser778Pro mutation, indicating a disruption of inside-out signaling by the mutation. In addition, transfectants expressing this β3 variant showed reduced αIIbβ3-mediated cell spreading on immobilized Fg, focal adhesion, and fibrin clot retraction (similar results were also reported in PMID: 7721884). PubMed:8080992

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP4

Patient P (PMID: 1438206) exhibited a lifelong bleeding tendency, including ecchymoses and bruising. Platelets failed to aggregate or bind fibrinogen in response to ADP, collagen or thrombin. Platelet count was normal. GPIIb/IIIa levels were >50% of normal as measured by SDS/PAGE. Surface expression measured by radiolabeled antibody was 44% of normal. PP4 not meet due to lack of information (agglutination with ristocetin was not reported).

PP3

The computational predictor REVEL gives a score of 0.567, which is below the ClinGen PD VCEP PP3 threshold of >0.7 and does not predict a damaging effect on ITGB3 function. And the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing.

PM3

Patient P is heterozygous for Ser778Pro, the other β3 allele was silent and a separate undiscovered defect was hypothesized.

Approved on: 2021-11-04

Published on: 2021-12-23

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