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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CA8602531

953045 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 579dcde6-1990-4355-8416-0bfb744926eb

Approved on: 2020-09-04

Published on: 2021-01-22

HGVS expressions

NM_000419.4:c.2915dup

NC_000017.11:g.44374691dup

CM000679.2:g.44374691dup

NC_000017.10:g.42452059dup

CM000679.1:g.42452059dup

NC_000017.9:g.39807585dup

NG_008331.1:g.19819dup

NM_000419.3:c.2915dup

NM_000419.5:c.2915dup

ENST00000262407.5:c.2915dup

ENST00000587295.5:n.253+1146dup

ENST00000588098.1:n.9dup

ENST00000592462.5:n.2426dup

Pathogenic

PVS1_Strong PS3 PM2_Supporting PP1 PM3 PP4_Strong

Evidence Links 4

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.4:c.2915dup variant in exon 28 causes a frameshift and results in premature termination in exon 30, Leu973AlafsTer63. In-vitro studies show absent integrin expression on the cell surface (PMID: 15748238). At least 5 individuals including a sibling pair with this variant have been reported in the literature. In summary, based on the evidence available at this time, the variant is classified as pathogenic. GT-specific criteria applied: PVS1_Strong, PS3, PM2_supporiting, PM3, PP1, PP4_strong.

PVS1_Strong

PVS1_strong is met because the variant is in exon 28 and results in termination of the mRNA transcript at amino acid position 1035 in exon 30 and is therefore not expected to undergo NMD. Based on the SVI decision tree, the termination occurs in the cytoplasmic domain and removes <10% of the protein but the entire transmembrane domain is altered which is part of the Platelet Disorders VCEP defined critical region and is expected to alter protein function.

PS3

Evidence from PMID: 15748238 meets criteria for PS3. Expression vectors bearing wild-type αIIb or αIIb with the insertion of an additional 'C' between nucleotides 2911 and 2916 were cotransfected into COS-7 cells with wild-type β3. Surface expression of the mutant αIIbβ3 complex was found to be absent by confocal microscopy, using PE‐labeled anti‐integrin αIIbβ3, and by flow cytometry, using PerCP‐labeled antiβ3. Immunoprecipitation and Endo-H sensitivity analyses revealed that the mutant αIIb did not mature but was able to form a complex with β3. Since there was absence of integrin expression on the cell surface, the authors suggest that the mutant αIIbβ3 complex must be degraded by the intrinsic quality control system in the ER.

Expression vectors bearing wild-type αIIb or αIIb with the insertion of an additional 'C' between nucleotides 2911 and 2916 were cotransfected into COS-7 cells with wild-type β3. Surface expression of the mutant αIIbβ3 complex was found to be absent by confocal microscopy, using PE‐labeled anti‐integrin αIIbβ3, and by flow cytometry, using PerCP‐labeled antiβ3. Immunoprecipitation and Endo-H sensitivity analyses revealed that the mutant αIIb did not mature but was able to form a complex with β3. Since there was absence of integrin expression on the cell surface, the authors suggest that the mutant αIIbβ3 complex must be degraded by the intrinsic quality control system in the ER. PubMed:15748238

PM2_Supporting

PM2 is not met based on gnomAD v2.1.1 because the variant is found in 2/18384 alleles, in the East Asian population and the threshold for PM2 is less than 1 in 10,000 alleles. However, gnomAD v3 includes an additional 3,134 alleles from the East Asian population without the variant, which brings this below the <1/10,000 allele frequency.

PP1

PP1 is met as the the 2 affected siblings, GT41a and GT41b, in PMID: 25728920 are compound heterozygous for this variant and Ala31ProfsTer2.

PP1 cannot be met because even though the phase is confirmed in trans, there is no segregation in an affected individual as the sibling shown in Table 4. is normal (-/-) PubMed:19691478

GT41a and GT41b are siblings compound heterozygous for this variant and Ala31ProfsTer2. The variants have been confirmed in trans (Supp Fig 2). PubMed:25728920

PM3

Two compound heterozygous siblings are reported with the pathogenic Ala31ProfsTer2 variant in trans with Leu973Alafs, with phase confirmation (PMID: 25728920). This variant was also determined to be in trans with pathogenic Arg782Ter but the phase was not confirmed (PMID: 28888044).

The proband in this paper is compound heterozygous for this variant and a splice region variant, c.2602-3C>G, confirmed in trans by sequencing of patient cDNA clones. This proband was not counted here to avoid circularity. PubMed:15748238

Patient GT18 is compound heterozygous for the paternally inherited c.2915dup in trans with 2 maternally inherited variants Leu343Pro and g.951. Since VUS Leu343Pro is in cis with VUS g.951G>A this prband is not used for PM3. PubMed:19691478

2 compound heterozygous siblings are reported with the pathogenic Ala31ProfsTer2 variant in trans, with phase confirmation. 1 pt PubMed:25728920

This variant was determined to be in trans with p.Arg584Ter in case No.1 and with Arg782Ter in case No. 3. Arg584Ter has been curated as a VUS, and does not meet PM2. Arg782Ter is curated as a pathogenic variant, the phase was not confirmed in Case 3. 0.5pt PubMed:28888044

PP4_Strong

PP4 is met (at least 5 probands from PMID: 25728920, 28888044, 19691478, 15748238) because it meets the bleeding and laboratory phenotype criteria including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3. At least one proband of PMID: 25728920 meets PP4_strong.

66yo Japanese male proband with a history of purpura and frequent nose bleeds. Platelet morphology was reported to be normal. Platelet aggregation with collagen and ADP was absent, but normal response was seen with ristocetin. Expression of αIIbβ3 measured by flow cytometry was reduced (3-7%) and by Western blotting showed no band for αIIb and remarkable reduced β3 levels. The proband was compound heterozygous for this variant and a splice site variant, c.2602-3C>G, confirmed in trans by sequencing patient cDNA clones. This appears to be the first report of the Leu973AlafsTer63 variant in a patient. PubMed:15748238

At least one bleeding phenotype was met among all patients and laboratory findings state that normal platelet count was found in all patients, there was absent or reduced aggregation in response to ADP, ADR, AA and collagen except ristocetin, and there was absent protein expression on the Western Blot. PubMed:19691478

2 siblings, GT41a & GT41b, are compound heterozygous for this variant and Ala31ProfsTer2. GT41a is a 15yo female patient of Canadian and Chinese origins with frequent and severe epistaxis requiring hospital treatment (platelet and rFVIIa transfusion, nasal support, anti-fibrinolytic treatment) and easy bruising, with a WHO bleeding score of 4. Platelet aggregation was absent with 3 agonists, but normal with ristocetin. αIIbβ3 expression assessed by flow cytometry was <5%. She was compound heterozygous for Leu973Alafster63 & Ala31ProfsTer2, phase not confirmed. GT41b is a 13yo male patient of Canadian and Chinese origins with epistaxis, ecchymoses, easy bruising and a WHO bleeding score of 2. Treatment included administration of rFVIIa and anti-fibrinolytics. Platelet aggregation was absent with 3 agonists, but normal with ristocetin. αIIbβ3 expression assessed by flow cytometry was <5%. He was compound heterozygous for Leu973Alafster63 & Ala31ProfsTer2, phase not confirmed. PubMed:25728920

2 compound heterozygous individuals (case No. 1 in trans with Arg584Ter; case No. 3 in trans with Arg782Ter) with severe bleeding symptoms including recurrent epistaxis, bleeding in oral cavity, and easy‐bruising spontaneously or after trauma, with normal platelet count and size. Platelet aggregation test was defective with all physiological agonists except ristocetin. Flow cytometry showed reduced integrin αIIbβ3 expression in both patients. PubMed:28888044

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