Variant: NM_000212.2(ITGB3):c.740G>A (p.Gly247Asp)

CA123256

13569 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 4385c6b6-e02a-42cd-8333-e5f3b6ce5f5c

Approved on: 2024-08-20

Published on: 2024-08-20

HGVS expressions

NM_000212.2:c.740G>A
NM_000212.2(ITGB3):c.740G>A (p.Gly247Asp)
NC_000017.11:g.47286385G>A
CM000679.2:g.47286385G>A
NC_000017.10:g.45363751G>A
CM000679.1:g.45363751G>A
NC_000017.9:g.42718750G>A
NG_008332.2:g.37544G>A
ENST00000696963.1:c.740G>A
ENST00000559488.7:c.740G>A
ENST00000559488.5:c.740G>A
ENST00000560629.1:c.705G>A
ENST00000571680.1:c.740G>A
NM_000212.3:c.740G>A

Uncertain Significance

• Met criteria codes: PS3_Supporting PP3 PM2_Supporting

• Not Met criteria codes: PP4 PM3

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

Evidence submitted by expert panel

Platelet Disorders VCEP

The ITGB3 missense variant NM_000212.3:c.740G>A replaces the glycine residue with an aspartate residue (p.Gly247Asp) and is absent from control population databases, including gonmADv4.1.0 (PM2_supporting). The variant is predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.963; PP3). The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-19% compared to wild type; PMID: 20020534; PS3_supporting). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-24 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and the second ITGB3 variant identified in the individual is of uncertain significance and unknown phase. In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3.

Met criteria codes

• PS3_Supporting: PMID: 20020534: ITGB3 cDNA carrying the c.740G>A variant was transiently transfected into COS-7 cells. αIIb, β3, and αIIbβ3 receptor expression on the cell surface was measured by flow cytometry. The number of cells positive for αIIb, β3, and αIIbβ3 was found to be reduced (estimated to be ~7-19% expression compared to wild type). This evidence was downgraded to PS3_Supporting because the level of αIIb, β3, and αIIbβ3 cell surface expression was not reported, only whether cells were positive or negative for surface αIIb, β3, and αIIbβ3.
• PP3: The REVEL score for this variant is 0.963, exceeding the VCEP-established threshold of ≥ 0.7 to apply PP3.
• PM2_Supporting: This is a rare variant not reported in control population databases, including gnomAD v4.1.0, meeting the criterion to apply PM2_supporting.

Not Met criteria codes

• PP4: This variant was reported in heterozygosity in one individual (CabGT-24, PMID: 20020534), however sufficient phenotypic information (bleeding phenotype, platelet aggregation) to meet PP4 were not provided.
• PM3: This variant has been observed in heterozygosity in one individual (CabGT-24 in PMID: 20020534) in combination with a second ITGB3 variant provisionally classified as a VUS by the Platelet Disorders VCEP (c.836A>T, p.Lys279Met), phase unconfirmed.