NM_000419.5:c.2800G>T

CA290946484

996165 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

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

Approved on: 2020-09-06

Published on: 2021-01-22

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: PS3_Moderate PM3_Supporting PM2_Supporting PP4_Strong

• Not Met criteria codes: PP3

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

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). This variant has been observed in a proband (PMID 25728920) with a phenotype specific for Glanzmann's thrombasthenia (GT) who also harbors a second ITGA2B variant (c.1413C>G, p.Tyr471Ter) previously classified by the VCEP as pathogenic (phase unconfirmed). Furthermore, this variant has not been observed in population databases (absent from gnomAD v2.1.1 and v3). Finally, expression of the variant in a heterologous cell line demonstrated significantly reduced surface protein expression via flow cytometry. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3_moderate, PM2_supporting, PM3_supporting, and PP4_strong.

Met criteria codes

• PS3_Moderate: Transient expression of the c.2800G>T (p.Val934Phe) variant in COS-7 cells and cell surface expression detection of αIIb, β3, and αIIbβ3 by flow cytometry demonstrated that the variant leads to markedly reduced αIIb, β3, and αIIbβ3 expression levels compared to wild type (PMID 20020534), satisfying PS3 at a reduced evidence strength of moderate (PS3_moderate).
• PM3_Supporting: This variant 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). This occurrence with phase unknown scores 0.5 points, meeting PM3 at the downgraded strength level of supporting (PM3_supporting). 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.
• PM2_Supporting: This variant is not observed in gnomAD v2.1.1 or v3, meeting criteria for PM2.
• PP4_Strong: All requirements for PP4 at an upgraded strength of moderate (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.

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 is not predicted to impact splicing (Human Splicing Finder and MaxEntScan).