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

CA400023344

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c49a54d1-519d-4936-ad13-a218a87cc99b

HGVS expressions

NM_000212.3:c.614+1G>T

ENST00000559488.7:c.614+1G>T

ENST00000559488.5:c.614+1G>T

ENST00000560629.1:n.579+1G>T

ENST00000571680.1:c.614+1G>T

NM_000212.2:c.614+1G>T

NC_000017.11:g.47284696G>T

CM000679.2:g.47284696G>T

NC_000017.10:g.45362062G>T

CM000679.1:g.45362062G>T

NC_000017.9:g.42717061G>T

NG_008332.2:g.35855G>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Pathogenic"

PM2_Supporting PVS1 PP4_Strong

PP1 PM3

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.614+1G>T variant on ITGB3 gene is a canonical splice donor variant that has been reported previously in the context of Glanzmann Thrombasthenia (PMID: 25728920). It is predicted to cause a disruption of the canonical donor splice site in intron 4 (PVS1). It is absent from all major population cohorts (gnomAD, ExAC and 1000Genomes; PM2_supporting). This variant has been reported in homozygosity in two symptomatic siblings who meet diagnostic criteria for GT phenotype (PMID: 25728920). However, the siblings are homozygous for both c.614+1G>T and Arg228His and while this splice variant is Likely Pathogenic an impact of the missense variant can not be excluded so this case has not been considered in the classification of this variant. This variant meets GT-specific criteria for PVS1 and PM2_supporting and is therefore classified as Likely Pathogenic.

PM2_Supporting

Absent in gnomAD database

PVS1

This variant is predicted to disrupt the canonical splice donor site in intron 4 resulting in skipping of exon 4. This is expected to cause a frameshift with premature stop at codon 122 (exon 5 of 15), therefore NMD would be expected.

PP4_Strong

Two related individuals(GT43a&b) had history of significant mucocutaneous bleeding, platelet aggregation was absent with three physiological agonists (but normal aggregation with ristocetin) and reduced (<5%) surface expression of αIIbβ3 demonstrated by flow cytometry. Sanger sequencing ensured coverage of exons and splice sites of the ITGA2B and ITGB3 genes as well as untranslated regions (UTR). (PMID: 25728920)

PP1

The homozygous c.614+1G>T and Arg288His variants were seen to segregate in two affected members of a family with GT. (PMID: 25728920) Patients GT43a&b are homozygous for both c.614+1G>T and Arg228His, because the effect of each variant can not be determined independently no criteria have been applied based on patient information.

PM3

The ITGB3 c.614+1G>T and Arg228His variants were found in homozygous state in two related members of a family with GT. 0.5 points. However, since patients GT43a&b are homozygous for both c.614+1G>T and Arg228His, because the effect of each variant can not be determined independently no criteria have been applied based on patient information.

Approved on: 2021-08-17

Published on: 2021-08-20

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.