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_000212.2(ITGB3):c.2248C>T (p.Arg750Ter)

CA123246

13564 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1080f71d-0827-4698-afdc-c5d1cea8c32e

HGVS expressions

NM_000212.2:c.2248C>T

NM_000212.2(ITGB3):c.2248C>T (p.Arg750Ter)

NC_000017.11:g.47307584C>T

CM000679.2:g.47307584C>T

NC_000017.10:g.45384950C>T

CM000679.1:g.45384950C>T

NC_000017.9:g.42739949C>T

NG_008332.2:g.58743C>T

ENST00000559488.7:c.2248C>T

ENST00000559488.5:c.2248C>T

ENST00000560629.1:n.2213C>T

NR_110880.1:n.363-3802G>A

NR_110881.1:n.227-3802G>A

NM_000212.3:c.2248C>T

NM_000212.3(ITGB3):c.2248C>T (p.Arg750Ter)

Pathogenic

PP4_Strong PVS1_Strong

PS3 PM3 PM2

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.2:c.2248C>T variant is a nonsense variant that results in premature termination of translation; however, NMD is not predicted. The variant is reported at a frequency of 0.0006008 in gnomAD v2.1.1 in the African population and does not meet PM2 or BS1 (PM2 threshold: <0.0001; BS1 threshold >0.00158). The variant is observed in one homozygous and 3 compound heterozygous individuals in the literature and from internal laboratory data (PMID: 20106508, 9351872, 30138987); however, evidence from the in-trans variatns is not applicable as Arg750Ter does not meet PM2. Functional evidence from PMID: 9351872 shows that the variant-expressing CHO cells bind fibrinogen but fail to spread on fibrinogen-coated surface. In summary, the Arg750Ter variant is classified as pathogenic. GT-specific criteria applied: PVS1_Strong, PP4_Strong.

PP4_Strong

Patient RM of PMID: 9351872 meets criteria for PP4_Strong, with bleeding phenotype, abnormal aggregometry to >2 agonists, but normal response to ristocetin, reduced αIIbβ3 expression (30-50%), but little to no PAC-1 binding and full sequencing of both ITGA2B and ITGB3 genes. Compound het patient (with c.79+1G>A) from internal lab data - 46yo African American male with iron deficiency anemia, history of easy bruising, gum bleeding, intermittent hematuria, bleeding with procedures and dental extractions. Platelet aggregation was markedly decreased with AA, ADP, collagen and epinephrine, while ristocetin response was mildly reduced. This patient does not meet PP4 criteria.

PVS1_Strong

This nonsense variant in exon 14 occurs just before the last 50 bases of the penultimate exon, suggesting that NMD is predicted. However, evidence from PMID: 9351872 shows that a truncated protein was made. PVS1_Strong is applied as Arg750 occurs in the cytoplasmic domain of β3, which is specified as a critical region by the Platelet Disorders VCEP.

PS3

PS3 is not applied as Arg750Ter expressing CHO cells showed normal surface expression of the αIIbβ3 complex by flow cytometry, with intact ligand-binding site and outside-in signaling. Cells bound fibrinogen in a dose-dependent manner, but failed to spread on fibrinogen-coated surface

PM3

1 homozygous proband (PMID: 20106508; potentially 0.5 pts) and 3 compound het probands (2 published [PMID: 9351872, 30138987; potentially 1 pt] and 1 from internal lab data [pathogenic, phase not confirmed; potentially 0.5 pts]) reported and may contribute evidence towards PM3. However, PM3 cannot be applied for this variant as it does not meet PM2.

PM2

The variant is reported in gnomAD v2.1.1 at a frequency of 0.0006008 (15/24968 African alleles) and in gnomAD v3 at a frequency of 0.0004521 (19/42028 African alleles) with 0 homozygotes. The gnomAD frequencies neither meet the PM2 cut-off (<0.0001) nor the BS1 cut-off (>0.00158).

Approved on: 2021-10-01

Published on: 2021-12-23

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.