The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_000212.2(ITGB3):c.1924G>T (p.Glu642Ter)

CA123249

13565 (ClinVar)

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
UUID: 0f7b571b-c808-4fac-a319-7b5206f29a55
Approved on: 2021-12-21
Published on: 2021-12-23

HGVS expressions

NM_000212.2:c.1924G>T
NM_000212.2(ITGB3):c.1924G>T (p.Glu642Ter)
NC_000017.11:g.47300488G>T
CM000679.2:g.47300488G>T
NC_000017.10:g.45377854G>T
CM000679.1:g.45377854G>T
NC_000017.9:g.42732853G>T
NG_008332.2:g.51647G>T
ENST00000559488.7:c.1924G>T
ENST00000559488.5:c.1924G>T
ENST00000560629.1:n.1889G>T
NM_000212.3:c.1924G>T
NM_000212.3(ITGB3):c.1924G>T (p.Glu642Ter)
More

Pathogenic

Met criteria codes 5
PM2_Supporting PP4_Moderate PS3_Supporting PM3 PVS1_Strong

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
NM_000212.2(ITGB3):c.1924G>T (p.Glu642Ter) in exon 12 of 15 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. However, RT-PCR analysis in the proband of PMID: 9845537 found that, instead, a shortened transcript was produced (in similar quantities to the normal allele) with in-frame skipping of exons 11 and 12 (reported by authors as exons 10 and 11, using alternate numbering), resulting in removal of 14% of the protein (PVS1_strong). CHO cells were transiently cotransfected with the plasmid pcDNA3-GPIIb and either WT or mutant pcDNA3-GPIIIa with this variant. To investigate the surface exposure of GPIIb-IIIa, intact cells were labeled with biotin, and the GPIIb-IIIa complexes were immunoprecipitated with anti-GPIIb (M3) or anti-GPIIIa (P37) MoAbs. No biotin-labeled products were found in cells cotransfected with normal GPIIb and mutant GPIIIa. Additionally, to examine the intracellular presence of GPIIb and/or GPIIIa as either monomers or heterodimers, total cell lysates were labeled with biotin, and GPIIb, GPIIIa, or GPIIb-IIIa complexes were immunoprecipitated. Unlike in extracts from cells coexpressing normal subunits, heterodimers failed to immunoprecipitate using a complex-specific MoAb, suggesting that the mutant ΔGPIIIa does not complex with GPIIb. Pulse-chase experiments further verified that the mutant ΔGPIIIa does not complex to GPIIb (PMID: 9845537; PS3_supporting). This variant has been detected homozygous in at least 2 probands with Glanzmann thrombasthenia (PMIDs: 14985172, 9845537; PM3). At least one patient (Patient II.1 in PMID: 14985172) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry and Western blot. This variant is absent from gnomAD v2.1.1 (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_strong, PS3_supporting, PP4_moderate, PM3, PM2_supporitng. (VCEP specifications version 2; date of approval 12/21/21).
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PP4_Moderate
At least one patient (Patient II.1 in PMID: 14985172) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry and Western blot. However, ITGA2B and ITGB3 were not sequenced across all exons and intron/exon boundaries.
PS3_Supporting
In PMID: 9845537 CHO cells were transiently cotransfected with the plasmid pcDNA3-GPIIb and either WT or mutant pcDNA3-GPIIIa. To investigate the surface exposure of GPIIb-IIIa, intact cells were labeled with biotin, and the GPIIb-IIIa complexes were immunoprecipitated with anti-GPIIb (M3) or anti-GPIIIa (P37) MoAbs. No biotin-labeled products were found in cells cotransfected with normal GPIIb and mutant GPIIIa. Additionally, to examine the intracellular presence of GPIIb and/or GPIIIa as either monomers or heterodimers, total cell lysates were labeled with biotin, and GPIIb, GPIIIa, or GPIIb-IIIa complexes were immunoprecipitated. Unlike in extracts from cells coexpressing normal subunits, heterodimers failed to immunoprecipitate using a complex-specific MoAb, suggesting that the mutant ΔGPIIIa does not complex with GPIIb. Pulse-chase experiments further verified that the mutant ΔGPIIIa does not complex to GPIIb. Downgraded to PS3_supporting because neither Western blot or flow cytometry were used to measure expression.
PM3
This variant has been detected homozygous in at least 2 probands with Glanzmann thrombasthenia (PMIDs: 14985172, 9845537; PM3).
PVS1_Strong
NM_000212.2(ITGB3):c.1924G>T (p.Glu642Ter) in exon 12 of 15 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). However, RT-PCR analysis in the proband of PMID: 9845537 found that, instead, a shortened transcript was produced (in similar quantities to the normal allele) with in-frame skipping of exons 11 and 12 (reported by authors as exons 10 and 11, using alternate numbering), resulting in removal of 14% of the protein.
Curation History
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.
¤ Powered by BCM's Genboree.