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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000419.4(ITGA2B):c.2870C>T (p.Ser957Leu)

CA115850

2902 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3c048343-6894-4a94-af04-658b0450a446

HGVS expressions

NM_000419.4:c.2870C>T

NM_000419.4(ITGA2B):c.2870C>T (p.Ser957Leu)

ENST00000262407.6:c.2870C>T

ENST00000648408.1:n.2301C>T

ENST00000262407.5:c.2870C>T

ENST00000587295.5:n.253+1101C>T

ENST00000592462.5:n.2381C>T

NM_000419.3:c.2870C>T

NM_000419.5:c.2870C>T

NC_000017.11:g.44374732G>A

CM000679.2:g.44374732G>A

NC_000017.10:g.42452100G>A

CM000679.1:g.42452100G>A

NC_000017.9:g.39807626G>A

NG_008331.1:g.19774C>T

Uncertain Significance

PM3_Supporting PS3_Supporting PM2_Supporting

PP4 PP3

Evidence Links 1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.2870C>T; p.Ser957Leu variant has been reported, in the homozygous state, in at least one proband (PMID: 20020534). It is absent from population databases ExAC and gnomAD. The Ser957Leu mutant complex was expressed in COS-7 cells and, in three replicates, expression of the complex (% positive cells) was assessed by flow cytometry, using antibodies to alpha-IIb, beta-3 or the complex, finding approximately 19% positive cells for the αIIbβ3 complex compared to WT. In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PS3_supporting, PM2_Supporting and PM3_Supporting.

PM3_Supporting

The Ser957Leu variant was observed once in the homozygous state (PMID: 20020534).

Patient 16 was homozygous for the Ser957Leu variant. 0.5pt PubMed:20020534

PS3_Supporting

The Ser957Leu mutant complex was expressed in COS-7 cells and, in three replicates, expression of the complex (% positive cells) was assessed by flow cytometry, using antibodies to alpha-IIb, beta-3 or the complex, finding approximately 19% positive cells for the αIIbβ3 complex compared to WT. This evidence was downgraded to PS3_Supporting because the level of αIIb, β3, and αIIbβ3 cell surface expression was not reported, only whether cells were positive or negative for surface αIIb, β3, and αIIbβ3.

The Ser957Leu mutant complex was expressed in COS-7 cells and, in three replicates, expression of the complex (% positive cells) was assessed by flow cytometry, using antibodies to alpha-IIb, beta-3 or the complex, finding approximately reduced positive cells compared to WT (28% αIIb, 52% β3, 19% αIIbβ3 complex). 19% positive cells for the complex is within the range of 5-25% determined by the VCEP. PubMed:20020534

PM2_Supporting

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PP4

PMID: 20020534 Patient cells were analyzed by flow cytometry for platelet glycoprotein (2% GP IIb, 10% GP IIIa, 100% GPIb) and fibrinogen (15%) content. The GT database reports aggregation was absent for ADP and collagen but normal with Ristocetin. No data was reported for bleeding phenotypes.

Cells from Patient 16, with Type I GT, were analyzed by flow cytometry for platelet glycoprotein (2% GP IIb, 10% GP IIIa, 100% GPIb) and fibrinogen (15%) content. No aggregometry results or bleeding phenotypes were reported in this publication. PubMed:20020534

PP3

REVEL score is 0.451 below the >0.7 threshold. Splice predictors (SpliceAI and MaxEntScan) do not predict this variant to have an impact on splicing.

Approved on: 2021-06-15

Published on: 2021-08-20

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.