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]

Link to SEPIO compliant JSON-LD document

CA400023596

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c89de113-f1ee-4763-b864-e97a20252268

Approved on: 2020-11-10

Published on: 2021-01-22

HGVS expressions

NM_000212.3:c.724C>T

NC_000017.11:g.47286369C>T

CM000679.2:g.47286369C>T

NC_000017.10:g.45363735C>T

CM000679.1:g.45363735C>T

NC_000017.9:g.42718734C>T

NG_008332.2:g.37528C>T

NM_000212.2:c.724C>T

ENST00000559488.5:c.724C>T

ENST00000560629.1:n.689C>T

ENST00000571680.1:c.724C>T

Pathogenic

PP4_Moderate PM2_Supporting PVS1

PM3

Evidence Links 1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

NM_000212.3(ITGB3):c.724C>T (p.Arg242Ter) is a stop-gain (nonsense) variant that has been reported previously in at least one proband who satisfies the diagnostic criteria for the GT phenotype (PMID: 22250950). MAF of this variant for the Non-Finnish European subpopulation is 0.000064 in gnomAD v2.1.1. This nonsense variant is predicted to cause NMD and loss of function. This variant meets GT specific criteria for PVS1, PM2_Supporting and PP4_moderate and is therefore classified as Pathogenic.

PP4_Moderate

Proband GT4 presented with mucocutaneous bleeding, showed a reduced expression of aIIbb3 expression (~10%) by flow cytometry and an absence of platelet aggregation to all physiological agonists except ristocetin. (PMID: 22250950) However, Since there is no information confirming full sequencing of ITGB3 and ITGA2B genes, PP4_Moderate is applied.

PubMed:22250950

PM2_Supporting

The overall AF in gnomAD v2.1.1 is 0.00003 (1/31396) and the MAF in the European (Non Finnish) subpopulation is 0.000064 (1/15426). This is below the recommended threshold of 0.01%.PM2_supporting applied.

PVS1

This is a nonsense (stop-gain) variant located in exon 5 of 15 that is predicted to cause NMD and loss of function.

PM3

This variant has been reported in compound heterozygosity with variant p.Cys624tyr (with phase unconfirmed), which has been classified as Pathogenic by ClinGen Platelet VCEP. (PMID:22250950) However, this evidence is not considered here to avoid circularity.

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