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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CA290949031

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a40726b4-c4be-45c5-890e-71ba90ba03b3

HGVS expressions

NM_000419.5:c.1879-2A>G

NC_000017.11:g.44378712T>C

CM000679.2:g.44378712T>C

NC_000017.10:g.42456080T>C

CM000679.1:g.42456080T>C

NC_000017.9:g.39811606T>C

NG_008331.1:g.15794A>G

NM_000419.3:c.1879-2A>G

NM_000419.4:c.1879-2A>G

ENST00000262407.5:c.1879-2A>G

ENST00000592462.5:n.674-2A>G

Pathogenic

PP4_Strong PM3 PM2_Supporting PP1_Moderate PVS1

PP3

Evidence Links 3

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The ITGA2B splice variant NM_000419.4:c.1879-2A>G alters a canonical splice acceptor site. This variant is expected to lead to exon 19 skipping and production of an mRNA product predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in a proband with a phenotype specific for Glanzmann's thrombasthenia (GT) and also observed to segregate with disease in three affected homozygous family members. Furthermore, this variant has not been observed in population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PM3, PP1_moderate, and PP4_strong.

PP4_Strong

All requirements for PP4 at an upgraded strength of strong (PP4_Strong) are met (PMID: 25728920, GT66): mucocutaneous bleeding; total lack of 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 splice sites of ITGA2B and ITGB3, as well as upstream regions.

PM3

This variant was reported in homozygosity in nine patients in the literature (PMID: 30792900, GT-25, GT-26, GT-35, GT-36, GT-37, GT-47, GT-48; PMID: 25728920, GT-66; PMID: 20020534, CabGT-9). Each homozygous occurrence has the potential to earn 0.5 points. However, based on ClinGen SVI guidance, the score for this evidence was capped at the maximum of 1.0 point (equivalent to PM3 at the default strength of moderate) for all homozygous cases to prevent overclassification of homozygous occurrences.

PubMed:20020534

PubMed:30792900

PubMed:25728920

PM2_Supporting

Variant not observed in gnomAD v2.1.1 or v3.

PP1_Moderate

This variant was reported to segregate with Glanzmann's Thrombasthenia in three homozygous individuals in a single family (FAM 09, patients GT-35, GT-36, GT-37; PMID: 30792900).

PVS1

This variant alters the canonical splice acceptor site and is predicted to result in skipping of exon 19, leading to a frameshift and introduction of a premature termination codon in exon 20 of 30. The resulting mRNA is predicted to be susceptible to nonsense-mediated decay.

PP3

Loss of the 3' splice acceptor site is predicted by both MaxEntScan (wild type sequence score: 7.58, variant sequence score: -0.38) and Human Splicing Finder (wild type sequence score: 78.86, variant sequence score: 50.99). However, PP3 was not applied in combination with PVS1 in order to avoid double counting predictive evidence.

Approved on: 2020-10-20

Published on: 2021-01-22

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