Evidence Repository - GenboreeKB

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

Variant: NM_000212.3(ITGB3):c.598G>A (p.Glu200Lys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA8622990

2073656 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f1322688-a9bf-45a7-b51f-9b0956214124

Approved on: 2023-12-19

Published on: 2023-12-19

HGVS expressions

NM_000212.3:c.598G>A

NM_000212.3(ITGB3):c.598G>A (p.Glu200Lys)

NC_000017.11:g.47284679G>A

CM000679.2:g.47284679G>A

NC_000017.10:g.45362045G>A

CM000679.1:g.45362045G>A

NC_000017.9:g.42717044G>A

NG_008332.2:g.35838G>A

ENST00000559488.7:c.598G>A

ENST00000559488.5:c.598G>A

ENST00000560629.1:c.563G>A

ENST00000571680.1:c.598G>A

NM_000212.2:c.598G>A

Uncertain Significance

PM2_Supporting BS3

PS3 PM3 BP4 PP3 PP4

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

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

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Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.598G>A variant in ITGB3 is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 200 (p.Glu200Lys). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00006684 (3/44884 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). A homozygous patient was reported with Glanzmann thrombasthenia in a thesis from The University of Sheffield (Sabi, 2016; https://etheses.whiterose.ac.uk/13584/). The patient has mucocutaneous bleeding symptoms, including epistaxis, however they also have macrothrombocytopenia (not consistent with GT) and no aggregation or surface expression data were reported to confirm the diagnosis. Additionally, the thesis reported functional studies; CHO cells were cotransfected with wild-type ITGA2B cDNA and variant ITGB3 cDNA, demonstrating similar surface expression, activation, and ligand binding, of αIIbβ3 to that observed in cells expressing the wild-type receptor (BS3). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BS3, PM2_Supporting (VCEP specifications version 2).

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.0.0 is 0.00006684 (3/44884 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).

BS3

Reported in a thesis from The University of Sheffield. CHO cells were cotransfected with wild-type ITGA2B cDNA and variant ITGB3 cDNA, demonstrating similar surface expression of αIIbβ3 to that observed in cells expressing the wild-type receptor. The ability of the recombinant αIIbβ3 receptors to undergo the conformational change that occurs on activation and to bind ligand was investigated by flow cytometry, using PAC-1 and fibrinogen. Cells expressing the p.Glu200Lys variant was able to bind to both PAC-1 and fibrinogen at levels that were comparable to those of wild-type. PAC-1 binding of cells expressing the p.Glu200Lys variant was similar to wild-type at all concentrations of DTT used to induce receptor activation . They did, however, show significant reductions in αvβ3 expression by 78% .

PS3

Reported in a thesis from The University of Sheffield. When seeded on immobilized fibrinogen, CHO cells expressing the p.Glu200Lys variant demonstrated increased formation of proplatelet-like protrusions and an increase in protrusion length compared to cells expressing wild-type β3. This may translate to an increase in the rate of proplatelet production, producing fewer, but larger platelets. This is not a PD-VCEP approved assay and does not address the functional defects related to Glanzmann thrombasthenia.

PM3

One homozygous patient has been reported from University of Sheffield (Sabi, 2016; https://etheses.whiterose.ac.uk/13584/). They are reported as a GT patient, however due to the presence of macrothrombocytopenia and the absence of reported aggregation results this patient is not considered here.

BP4

The computational predictor REVEL gives a score of 0.288, which is above the ClinGen PD VCEP threshold of <0.25.

PP3

The computational predictor REVEL gives a score of 0.288, which is below the ClinGen PD VCEP PP3 threshold of >0.7 and does not predict a damaging effect on ITGB3 function. And the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. Additionally, the potential for the c.598G>A nucleotide change to affect ITGB3 RNA splicing was investigated using ESE-finder and RESCUE-ESE (thesis from The University of Sheffield). Both the wild-type and mutated minigenes resulted in the inclusion of the middle exon of the spliced transcript, suggesting the c.598G>A mutation does not disturb the ESE site within the ITGB3 gene.

PP4

A GT patient is reported in a thesis from University of Sheffield (Sabi, 2016; https://etheses.whiterose.ac.uk/13584/). The patient has mucocutaneous bleeding symptoms, including epistaxis, however no aggregation or surface expression data were reported.

Curation History

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