Variant: NM_000419.5:c.2800G>T

CA290946484

996165 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 0ee33e3f-bcc1-498a-87da-e7f0c797c10b

Approved on: 2024-06-06

Published on: 2024-06-07

HGVS expressions

NM_000419.5:c.2800G>T
NC_000017.11:g.44375039C>A
CM000679.2:g.44375039C>A
NC_000017.10:g.42452407C>A
CM000679.1:g.42452407C>A
NC_000017.9:g.39807933C>A
NG_008331.1:g.19467G>T
ENST00000262407.6:c.2800G>T
ENST00000648408.1:c.2231G>T
ENST00000262407.5:c.2800G>T
ENST00000587295.5:c.253+794G>T
ENST00000592462.5:n.2074G>T
NM_000419.3:c.2800G>T
NM_000419.4:c.2800G>T

Likely Pathogenic

• Met criteria codes: PP4_Strong PM3 PM2_Supporting PS3_Supporting

• Not Met criteria codes: PP3

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 ITGA2B missense variant NM_000419.5:c.2800G>T replaces the valine residue with a phenylalanine residue (p.Val934Phe). All requirements for PP4 at an upgraded strength of strong (PP4_Strong) are met by proband GT20 (PMID 25728920): epistaxis; absent platelet aggregation in response to physiologic agonists except normal response to ristocetin; flow cytometry showed 10-20% expression of αIIbβ3; direct sequencing of all exons and splice sites of ITGA2B and ITGB3, as well as upstream regions. This variant has also been observed in a homozygous proband (PMID: 34347927) and a proband (PMID: 25728920) who also harbors a second ITGA2B variant (c.1413C>G, p.Tyr471Ter) previously classified by the VCEP as pathogenic (phase unconfirmed) (PM3). Furthermore, this variant has not been observed in population databases (absent from gnomAD v4.1.0; PM2_supporting). Finally, a functional study of this variant has been reported (PMID: 20020534; flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGA2B cDNA carrying this variant), finding approximately 20% positive cells for the β3 subunit compared to WT (PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PM3, and PP4_strong.

Met criteria codes

• PP4_Strong: All requirements for PP4 at an upgraded strength of strong (PP4_Strong) are met by proband GT20 (PMID 25728920): epistaxis; absent platelet aggregation in response to physiologic agonists except normal response to ristocetin; flow cytometry showed 10-20% expression of αIIbβ3; direct sequencing of all exons and splice sites of ITGA2B and ITGB3, as well as upstream regions.
• PM3: One homozygous patient has been reported (PMID: 34347927) 0.5pt. This variant also has been observed in a proband harboring a second VCEP-classified pathogenic variant (c.1413C>G, p.Tyr471Ter), however the phase of the variants was unconfirmed (PMID 20020534) 0.5 points. This variant has also been observed in a proband with a second variant, p.Gly401Cys (proband GT18, PMID 25728920). However, this evidence contributed to PM3 for p.Gly401Cys and was not counted for p.Val934Phe to avoid circularity. Total 1pt (PM3)
• PM2_Supporting: This variant is not observed in gnomAD v4.1.0 (PM2_supporting).
• PS3_Supporting: PMID: 20020534: ITGB3 cDNA carrying the c.2800G>T 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. In three replicates, expression of the complex (% positive cells) was assessed by flow cytometry, using antibodies to alpha-IIb, beta-3 or the complex, finding approximately 20% positive cells for the β3 subunit compared to WT. 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.

Not Met criteria codes

• PP3: The REVEL score for this variant (0.46) does not meet the VCEP-established threshold of ≥0.7 for PP3 and the variant is not predicted to impact splicing (SpliceAI delta scores 0.00-0.01).