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]

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CA8622899

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2adf80d1-0f96-497c-bc2e-08c9c9d53c0a

Approved on: 2020-09-04

Published on: 2021-01-28

HGVS expressions

NM_000212.2:c.224del

NC_000017.11:g.47283412del

CM000679.2:g.47283412del

NC_000017.10:g.45360778del

CM000679.1:g.45360778del

NC_000017.9:g.42715777del

NG_008332.2:g.34571del

NM_000212.3:c.224del

ENST00000559488.5:c.224del

ENST00000560629.1:n.189del

ENST00000571680.1:c.224del

Pathogenic

PM3 PP4_Strong PVS1 PM2_Supporting

PP1

Evidence Links 2

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The ITGB3 c.224del (p.Cys75Leufs) frameshift variant has been reported homozygous in at least 2 GT probands (PMIDs: 25728920, 12083483). It is predicted to undergo NMD due to creation of a premature stop codon in exon 3. The overall allele frequency in gnomAD is extremely low at 0.000003977, with a MAF of 0.000008795 in the non-Finnish European population. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PVS1,PM2_supporting, PM3, and PP4_strong.

PM3

At least 2 probands have been reported (PMID: 25728920 and PMID: 12083483) homozygous for c.224del. 0.5+0.5=1pt

Patient GT61 is homozygous for c.224del. PubMed:25728920

Patient MR is homozygous for c.224del. PubMed:12083483

PP4_Strong

Two probands have been reported (PMID: 12083483, PMID: 25728920) meeting criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

Patient GT61, homozygous for c.224del, had a history of mucocutaneous bleeding (including easy bruising, tonsil bleeding and menorrhagia) and a WHO bleeding score of 3. There was absent platelet aggregation with at least three agonists but normal ristocetin-induced aggregation. Severely reduced (<5%) platelet expression of alphaIIb-beta3 was confirmed by flow cytometry. No mention was made of platelet count. PubMed:25728920

Patient MR, homozygous for c.224del, had moderate bleeding severity (including gastrointestinal bleeding, as reported in the GT database entry 98). Platelet aggregation was absent in response to ADP, epinephrine, and Thrombin, but normal for Ristocetin. Platelet surface expression, measured by flow cytometry, was <10% for GPIIb and GPIIIa. PubMed:12083483

PVS1

This frameshift variant introduces a premature stop codon in exon 3 of 15. The resulting mRNA product is predicted to undergo nonsense mediated decay.

PM2_Supporting

The overall allele frequency in gnomAD is 0.000003977, with a MAF of 0.000008795 in the non-Finnish European population (1/113,702 alleles). This is below the <1/10,000 allele maximum.

PP1

Patient GT61 of PMID: 25728920 had an affected brother however his genotype was not reported.

Patient GT61 had an affected brother however his genotype was not reported. PubMed:25728920

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