Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000212.3:c.191G>A

CA291224490

1210201 (ClinVar)

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 1d619dd4-c055-4e5b-9008-b71ac01d963d
Approved on: 2024-08-20
Published on: 2024-08-20

HGVS expressions

NM_000212.3:c.191G>A
NC_000017.11:g.47283379G>A
CM000679.2:g.47283379G>A
NC_000017.10:g.45360745G>A
CM000679.1:g.45360745G>A
NC_000017.9:g.42715744G>A
NG_008332.2:g.34538G>A
ENST00000696963.1:c.191G>A
ENST00000559488.7:c.191G>A
ENST00000559488.5:c.191G>A
ENST00000560629.1:c.156G>A
ENST00000571680.1:c.191G>A
NM_000212.2:c.191G>A
More

Uncertain Significance

Met criteria codes 3
PP3 PS3_Supporting PM2_Supporting
Not Met criteria codes 2
PP4 PM3

Evidence Links 1

Expert Panel

Criteria Specification Information

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The ITGB3 missense variant NM_000212.3:c.191G>A replaces the cysteine residue with a tyrosine residue (p.Cys64Tyr). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-21 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and a second ITGB3 variant was not identified. The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-15% compared to wild type; PMID: 20020534; PS3_supporting). The variant is also absent from control population databases including gnomADv4.1.0 (PM2_supporting) and predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.981; PP3). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3.
Met criteria codes
PP3
The REVEL score for this variant is 0.981, exceeding the VCEP-established threshold of ≥ 0.7 to apply PP3.
PS3_Supporting
PMID: 20020534: ITGB3 cDNA carrying the c.191G>A variant was transiently transfected into COS-7 cells. αIIb, β3, and αIIbβ3 receptor expression on the cell surface was measured by flow cytometry. The number of cells positive for αIIb, β3, and αIIbβ3 was found to be reduced (estimated to be ~7-15% expression compared to wild type). 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. Furthermore, Western blot analyses of protein lysates from COS-7 cells transiently transfected with ITGB3 cDNA containing the c.191G>A variant revealed the presence of both αIIb (detected with antibody SZ22) and β3 (detected with antibody XIIF9), however both proteins had altered mobility relative to wild type β3. Additionally, two other antibodies with epitopes located in β3 amino acids stretches 49–98 (SZ21 and AP3) were not able to recognize ITGB3 protein containing the p.Cys64Tyr variant, despite reacting with normal β3 expressed in platelet cells and wild type αIIbβ3-transfected COS-7 cells. The authors suggest this could be a consequence of structural modifications induced by the C16–C38 disulfide bond disruption, which may lead to impaired αIIbβ3 complex formation or protein retention inside the cell.
COS-7 cells transiently transfected with ITGB3 cDNA containing the c.191G>A variant were analyzed by flow cytometry to measure the number of cells positive for αIIb, β3, and αIIbβ3 complex and found to have markedly reduced cell surface expression levels of each protein (estimated to be ~7-15% expression compared to wild type). Western blot analyses of protein lysates from COS-7 cells transiently transfected with ITGB3 cDNA containing the c.191G>A variant revealed the presence of both αIIb (detected with antibody SZ22) and β3 (detected with antibody XIIF9), however both proteins had altered mobility relative to wild type β3. Additionally, two other antibodies with epitopes located in β3 amino acids stretches 49–98 (SZ21 and AP3) were not able to recognize ITGB3 protein containing the p.Cys64Tyr variant, despite reacting with normal β3 expressed in platelet cells and wild type αIIbβ3-transfected COS-7 cells. PubMed:20020534
PM2_Supporting
This is a rare variant not reported in control population databases, including gnomAD v4.1.0, meeting the criterion to apply PM2_supporting.
Not Met criteria codes
PP4
This variant was reported in heterozygosity in one individual (CabGT-21, PMID: 20020534), however sufficient phenotypic information (bleeding phenotype, platelet aggregation) to meet PP4 were not provided.
PM3
This variant was reported in heterozygosity in one individual (CabGT-21 in PMID: 20020534), however a second ITGB3 variant was not identified.
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.