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.1199G>A (p.Cys400Tyr)

CA123244

13562 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c4ac081e-5a79-4468-b274-f8d363e98a9a

HGVS expressions

NM_000212.2:c.1199G>A

NM_000212.2(ITGB3):c.1199G>A (p.Cys400Tyr)

NC_000017.11:g.47291027G>A

CM000679.2:g.47291027G>A

NC_000017.10:g.45368393G>A

CM000679.1:g.45368393G>A

NC_000017.9:g.42723392G>A

NG_008332.2:g.42186G>A

ENST00000559488.7:c.1199G>A

ENST00000559488.5:c.1199G>A

ENST00000560629.1:n.1164G>A

ENST00000571680.1:c.1199G>A

NM_000212.3:c.1199G>A

NM_000212.3(ITGB3):c.1199G>A (p.Cys400Tyr)

Likely Pathogenic

PM2_Supporting PP1 PP3 PP4_Strong PM3

PS3

Evidence Links 2

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.1199G>A (p.Cys400Tyr) missense has been identified in at least 3 probands, including GT11 and GT15a of PMID: 29675921 meeting the criteria for PP4_strong. Siblings GT15a and GT15b are both compound heterozygous for Cys400Tyr and pathogenic variant c.1525del (PP1; PMID: 29675921). Additionally, Patient 34 of the GT database (and PMID:87814) is homozygous for Cys400Tyr (PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.968, which predicts a damaging effect on ITGB3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3, PP1, PP3, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx)

PM2_Supporting

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

PP1

Siblings GT15a and GT15b are both compound heterozygous for Cys400Tyr and c.1525del (PMID: 29675921).

PP3

The computational predictor REVEL gives a score of 0.968, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on ITGB3 function (PP3).

PP4_Strong

GT11 and GT15a of PMID: 29675921 meet the criteria for PP4_strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

PM3

Patient 34 of the GT database (and PMID:87814) is homozygous for Cys400Tyr 0.5pt GT15a of . PMID: 29675921 is compound heterozygous for Cys400Tyr and c.1525del (classified Pathogenic by the PD-VCEP). Confirmation of trans phase was not reported 0.5pt Total: 1pt (PM3).

PS3

Transfection studies in both PMID: 8781422 and PMID: 11806996 showed reduced surface expression but did not meet the PS3_moderate criteria. Additionally, both studies found fibrinogen binding was unaffected.

Transient transfection studies in Chinese hamster ovary cells indicated that the mutation results in an 85% to 90% reduction in αIIbβ3 surface expression, but these cells retain the ability to mediate adhesion to immobilized fibrinogen. Surface expression was assessed using radiolabeled antibodies specific for GPIIIa alone (125I-7H2) or the GPIIb/IIIa complex (125I-10E5) (not by flow cytometry or Western blot). PubMed:8781422

Wild-type or Cys400Tyr mutant β3 construct was cotransfected into human embryonic kidney 293 cells (106cells) with wild-type αIIb. Cell surface expression of the complex was assessed by flow cytometry at 25-30% expression of αIIbβ3 compared to WT. This is above the <25% threshold set by the PD-VCEP. Additionally, this variant did not impair ligand binding as measured by binding of FITC-fibrinogen. PubMed:11806996

Approved on: 2021-06-30

Published on: 2021-12-23

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