Variant: NM_000212.3:c.652C>T

CA400023445

1330327 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 87d75123-1e7c-450f-b9fd-e0c2884cee2e

Approved on: 2024-09-05

Published on: 2024-09-30

HGVS expressions

NM_000212.3:c.652C>T
NC_000017.11:g.47286297C>T
CM000679.2:g.47286297C>T
NC_000017.10:g.45363663C>T
CM000679.1:g.45363663C>T
NC_000017.9:g.42718662C>T
NG_008332.2:g.37456C>T
ENST00000696963.1:c.652C>T
ENST00000559488.7:c.652C>T
ENST00000559488.5:c.652C>T
ENST00000560629.1:c.617C>T
ENST00000571680.1:c.652C>T
NM_000212.2:c.652C>T

Uncertain Significance

• Met criteria codes: PM3_Supporting PP4_Moderate PM2_Supporting 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 ITGB3 missense variant NM_000212.3:c.652C>T replaces the histidine residue with a tyrosine residue (p.His218Tyr). This variant has been observed in homozygosity in one individual (PM3_supporting) with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT17, PMID: 16463284). All requirements for PP4_Moderate are met (GT17 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. This variant is absent from population databases, including gnomADv4.1.0 (PM2_supporting), and the in silico meta-predictor REVEL score for this variant is 0.938, exceeding the VCEP-established threshold of ≥0.7 and suggestive of a damaging effect on protein function (PP3). 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: PP4_moderate, PM2_supporting, PM3_supporting, and PP3.

Met criteria codes

• PM3_Supporting: This variant was reported in homozygosity in one individual (GT17 in PMID: 16463284), sufficient to apply PM3_Supporting.
• PP4_Moderate: All requirements for PP4_Moderate are met (GT17 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin.
• PM2_Supporting: This variant is absent from all population cohorts in gnomADv4.1.0 (PM2_supporting)
• PP3: This variant has a REVEL score of 0.938, exceeding the VCEP-established threshold of ≥0.7 and meeting the criteria for PP3.