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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CA291224896

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e8865ad9-beb0-4f47-acfe-18d84f3d1c9b

HGVS expressions

NM_000212.3:c.725G>A

NC_000017.11:g.47286370G>A

CM000679.2:g.47286370G>A

NC_000017.10:g.45363736G>A

CM000679.1:g.45363736G>A

NC_000017.9:g.42718735G>A

NG_008332.2:g.37529G>A

ENST00000559488.7:c.725G>A

ENST00000559488.5:c.725G>A

ENST00000560629.1:n.690G>A

ENST00000571680.1:c.725G>A

NM_000212.2:c.725G>A

Pathogenic

PP3 PM3 PP4_Strong PM2_Supporting PS3_Moderate

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_000212.3(ITGB3):c.725G>A (p.Arg242Gln) missense variant has a REVEL score of 0.859, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). Surface expression of αIIbβ3 measured by flow cytometry in 293 cells transiently co-transfected with Arg242Gln (here referred to as Arg216Gln) variant β3 and wild type αIIb showed decreased expression at approximately 20% of WT levels indicating that this variant impacts protein function (PMID: 11806996; PS3_moderate). It is absent from gnomAD v2.1.1 (PM2_Supporting). At least 2 GT patients homozygous for this variant have been reported in PMID: 9215749 and PMID: 19691478 (PM3). And At least one patient (Patient GT4 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry and function was pathological. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_moderate, PP4_strong, PM2_supporting, PM3, PP3. (VCEP specifications version 2; date of approval 02/03/2022)

PP3

The computational predictor REVEL gives a score of 0.859, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).

PM3

At least 2 homozygotes have been reported in PMID: 9215749 and PMID: 19691478 (PM3).

PP4_Strong

At least one patient (Patient GT4 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry and function was pathological. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong).

PM2_Supporting

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

PS3_Moderate

Surface expression of αIIbβ3 measured by flow cytometry in 293 cells transiently co-transfected with Arg242Gln (here referred to as Arg216Gln) variant β3 and wild type αIIb showed decreased expression at approximately 20% of WT levels indicating that this variant impacts protein function (PMID: 11806996; PS3_moderate).

Surface expression of αIIbβ3 measured by flow cytometry in [293 cells transiently co-transfected with Arg242Gln (here referred to as Arg216Gln) variant β3 and wild type αIIb showed decreased expression at approximately 20% of WT levels indicating that this variant impacts protein function. PubMed:11806996

Approved on: 2022-04-07

Published on: 2022-12-07

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