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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CA291224483

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8faa4bfc-7dfe-4b4c-82b4-29c9556d543d

HGVS expressions

NM_000212.3:c.166-2A>G

NC_000017.11:g.47283352A>G

CM000679.2:g.47283352A>G

NC_000017.10:g.45360718A>G

CM000679.1:g.45360718A>G

NC_000017.9:g.42715717A>G

NG_008332.2:g.34511A>G

NM_000212.2:c.166-2A>G

ENST00000559488.5:c.166-2A>G

ENST00000560629.1:n.131-2A>G

ENST00000571680.1:c.166-2A>G

Pathogenic

PP4_Strong PVS1 PM3 PM2_Supporting

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 ITGB3 splice acceptor variant NM_000212.3:c.166-2A>G is predicted to lead to skipping of exon 3, causing a frameshift that introduces a premature termination codon. The resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in two individuals (CabGT-19 in PMID: 20020534 and GT6 in PMID: 25373348), at least one of which was reported to have a phenotype specific for Glanzmann's thrombasthenia (GT). Furthermore, the variant is absent from control population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM3, PP4_strong, and PM2_supporting.

PP4_Strong

This variant was reported in homozygosity in individuals in three publications: GT6 in PMID: 25373348, CabGT-19 in PMID: 20020534, and the proband in PMID: 16907879. At least one of these individuals (GT6, PMID: 25373348) meets all requirements for PP4 at an upgraded strength of strong (PP4_Strong): severe bleeding symptoms; absent platelet aggregation in response to physiologic agonists except normal response to ristocetin; flow cytometry showed <5% expression of αIIbβ3; direct sequencing of all exons and intron/exon boundaries of ITGA2B and ITGB3.

PVS1

This variant alters the canonical splice acceptor located at the 3' end of intron 2/the 5' end of exon 3 and is predicted to lead to skipping of exon 3, resulting in a frameshift and introduction of a premature termination codon 23 amino acids residues downstream in exon 4. The resulting mRNA is predicted to be susceptible to nonsense-mediated decay, meeting the criteria for PVS1.

PM3

This variant was reported in homozygosity in two individuals (CabGT-19 in PMID: 20020534 and GT6 in PMID: 25373348). Each occurrence earns 0.5 points for a total of 1 point, sufficient to apply PM3. Although two additional publications report on an individual with this variant (PMID: 16907879 and PMID: 29884513), they are suspected to be the same individual originally reported as CabGT-19. Therefore, no additional points were awarded for these occurrences.

PM2_Supporting

This is a rare variant not reported in any control population databases, including gnomAD v2.1.1, gnomAD v3, PAGE, 1000 Genomes, and ESP, meeting the criterion to apply PM2_supporting.

Approved on: 2020-10-14

Published on: 2021-01-13

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