Evidence Repository
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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CA8623016

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: b2194a84-f0e0-4aba-a7ea-46f0f3c3f5dd
Approved on: 2023-01-17
Published on: 2023-02-15

HGVS expressions

NM_000212.3:c.655G>A
NC_000017.11:g.47286300G>A
CM000679.2:g.47286300G>A
NC_000017.10:g.45363666G>A
CM000679.1:g.45363666G>A
NC_000017.9:g.42718665G>A
NG_008332.2:g.37459G>A
ENST00000559488.7:c.655G>A
ENST00000559488.5:c.655G>A
ENST00000560629.1:n.620G>A
ENST00000571680.1:c.655G>A
NM_000212.2:c.655G>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PP3 PM3 PM2_Supporting PP4_Moderate
Not Met criteria codes 2
PS3 BS3

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The NM_000212.3(ITGB3):c.655G>A (p.Val219Met) missense variant has been reported in at least one patient (Patient GTa, PMID:11722423) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). GTa is compound heterozygous for this variant and pathogenic variant c.602del (PM3). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00003266 (1/30616) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (PM2_Supporting). The computational predictor REVEL gives a score of 0.874, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3, PP4_moderate, and PP3.
Met criteria codes
PP3
The computational predictor REVEL gives a score of .874, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).
PM3
This variant has been detected in at least 1 proband with Glanzmann thrombasthenia. For one of those individuals, one was compound heterozygous for this variant and a pathogenic variant c.602delA, confirmed in trans by cloning and sequencing of PCR amplified cDNA (PMID:11722423). Total points: 1 (PM3).
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003266 (1/30616) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).
PP4_Moderate
At least one patient (Patient GTa in PMID:11722423) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries.
Not Met criteria codes
PS3
Surface expression of αIIbβ3 measured by flow cytometry in HEK293T cells transiently co-transfected with Val193Met variant β3 and wild type β3 showed equal expression at 100% (>75%), (PMID:11722423).
Surface expression of αIIbβ3 measured by flow cytometry in HEK293T cells transiently co-transfected with Val193Met variant β3 and wild type β3 showed equal expression PubMed:11722423
BS3
Surface expression of αIIbβ3 measured by flow cytometry in HEK293T cells transiently co-transfected with Val193Met variant β3 and wild type β3 showed equal expression at 100% (>75%). Additionally, the receptor function of αIIbβ3, measured by functional flow cytometry, showed enhanced binding to 3H-SC52012 (a GPIIb/IIIa antagonist), however this assay does not meet the requirements for use by the ClinGen Platelet Disorders VCEP (PMID:11722423).
Surface expression of αIIbβ3 measured by flow cytometry in HEK293T cells transiently co-transfected with Val193Met variant β3 and wild type β3 showed equal expression PubMed:11722423
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