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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CA626684825

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 549f1ce3-ed8e-471a-b899-8e5e43282d09

HGVS expressions

NM_000212.3:c.225_226del

NC_000017.11:g.47283413_47283414del

CM000679.2:g.47283413_47283414del

NC_000017.10:g.45360779_45360780del

CM000679.1:g.45360779_45360780del

NC_000017.9:g.42715778_42715779del

NG_008332.2:g.34572_34573del

ENST00000559488.7:c.225_226del

ENST00000559488.5:c.225_226del

ENST00000560629.1:n.190_191del

ENST00000571680.1:c.225_226del

NM_000212.2:c.225_226del

Pathogenic

PM3_Supporting PM2_Supporting PVS1 PP4_Moderate

Evidence Links 0

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.225_226del (p.Ala76ProfsTer10) in exon 3 of ITGB3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3/15 and is predicted to lead to nonsense mediated decay (PVS1). GT7 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 0.3%, as measured by flow cytometry. GT7 (PMID: 32237906) is compound heterozygous for c.225_226del and Arg242Ter (classified Pathogenic by the PD-VCEP; PM3_supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001087 (2/18394 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 11/04/2021)

PM3_Supporting

GT7 (PMID: 32237906) is compound heterozygous for c.225_226del and Arg242Ter (classified Pathogenic by the PD-VCEP). Confirmation of trans phase was not reported.

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001087 (2/18394 alleles) in the East Asian population, an additional 2820 alleles in gnomAD v3.1.1 did not have the variant for a total of 2/21214 alleles or 0.000942, which is below the ClinGen PD VCEP threshold (<0.0001).

PVS1

The c.225_226del (p.Ala76ProfsTer10) variant in exon 3 of ITGB3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

PP4_Moderate

GT7 (PMID: 32237906) displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 0.3%, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries.

Approved on: 2021-11-09

Published on: 2021-12-23

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