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.719G>A (p.Arg240Gln)

CA123224

13553 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 896337ce-7c9e-40dc-89f7-3550c3ed61e6

HGVS expressions

NM_000212.2:c.719G>A

NM_000212.2(ITGB3):c.719G>A (p.Arg240Gln)

NC_000017.11:g.47286364G>A

CM000679.2:g.47286364G>A

NC_000017.10:g.45363730G>A

CM000679.1:g.45363730G>A

NC_000017.9:g.42718729G>A

NG_008332.2:g.37523G>A

ENST00000559488.7:c.719G>A

ENST00000559488.5:c.719G>A

ENST00000560629.1:n.684G>A

ENST00000571680.1:c.719G>A

NM_000212.3:c.719G>A

Pathogenic

PP4_Moderate PS3 PP3 PM2_Supporting PM3

PM5

Evidence Links 0

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.719G>A (p.Arg240Gln) missense variant has been reported in at least four patients (PMIDs: 1371279, 29084015, 29675921, 30138987) with a phenotype highly specific to GT. This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP and is predicted to have a deleterious effect (REVEL score 0.819). The functional impact has been assessed by transfection in CHO cells, showing normal αIIbβ3 surface expression with a deficiency in binding of fibrinogen and PAC-1 in response to mAb 62 stimulation (PMID: 1371279). In summary this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS3, PM2_Supporting, PM3, PP3, and PP4_Moderate.

PP4_Moderate

At least two probands, from PMID: 1371279 and PMID: 29675921, meet the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally in the patient from PMID: 1371279, there was normal surface expression of dysfunctional αIIbβ3, which failed to bind the ligand mimetic antibody PAC-1 as assessed by flow cytometry, however only the two regions of interest in ITGB3 were selected for sequence analysis so the presence of additional variants in the patient can not be ruled out.

PS3

Recombinant αIIbβ3 with Arg240Gln (here reported as Arg214Gln) was expressed in CHO cells, resulting in normal surface expression with a deficiency in binding of fibrinogen and PAC-1 in response to mAb 62 stimulation. WT PAC-1 binding assessed by flow cytometry increased from 25 to 66 arbitrary fluorescence units in response to mAb 62, while Arg240Gln αIIbβ3 remained at 25 units.

PP3

The REVEL score for this variant is 0.819, exceeding the VCEP-established threshold of >0.7 to support a deleterious effect.

PM2_Supporting

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PM3

At least three probands, from PMID: 1371279, PMID: 29084015, and PMID: 29675921, are homozygous for Arg240Gln. An additional patient (PMID: 30138987) is compound heterozygous with the Arg750Ter variant, however Arg705Ter is not sufficiently rare in all populations (above PM2 threshold) to consider for PM3.

PM5

Arg240Trp (classified Likely Pathogenic by the PD-EP) occurs at the same residue as Arg240Gln but is not considered here to avoid circularity.

Approved on: 2021-07-08

Published on: 2021-08-19

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