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

  • See Evidence submitted by expert panel for details.

Variant: NM_000212.2(ITGB3):c.836A>T (p.Lys279Met)

CA123254

13568 (ClinVar)

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
UUID: 5a767207-8239-464f-a198-590b669dbabb
Approved on: 2021-08-17
Published on: 2021-08-19

HGVS expressions

NM_000212.2:c.836A>T
NM_000212.2(ITGB3):c.836A>T (p.Lys279Met)
NC_000017.11:g.47287128A>T
CM000679.2:g.47287128A>T
NC_000017.10:g.45364494A>T
CM000679.1:g.45364494A>T
NC_000017.9:g.42719493A>T
NG_008332.2:g.38287A>T
ENST00000696963.1:c.836A>T
ENST00000559488.7:c.836A>T
ENST00000559488.5:c.836A>T
ENST00000560629.1:c.801A>T
ENST00000571680.1:c.836A>T
NM_000212.3:c.836A>T
More

Uncertain Significance

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

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The ITGB3 missense variant NM_000212.3:c.836A>T replaces the lysine residue with a methionine residue (p.Lys279Met) and is absent from control population databases. The variant is predicted by in silico tools to be damaging to protein function. 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 cells positive for the αIIbβ3 complex (estimated to be ~7% compared to wild type; PMID: 20020534). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-24 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and the second ITGB3 variant identified in the individual is of uncertain significance and unknown phase. 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
PM2_Supporting
This variant is rare in control population databases. It was observed in heterozygosity in a single individual in gnomAD v2.1.1 (MAF in African population: 0.00006152 (1/16256 alleles); overall allele frequency: 0.000003978 (1/251402 alleles)) and, similarly, in heterozygosity in a single individual in gnomad v3 (MAF in African population: 0.00002380 (1/42022 alleles); overall allele frequency: 0.000006979 (1/143292 alleles)). This frequency is below the VCEP-established threshold of fewer than 1 in 10,000 alleles, meeting the criterion to apply PM2_supporting.
PP3
The REVEL score for this variant is 0.744, exceeding the VCEP-established threshold of ≥ 0.7 to apply PP3.
PS3_Supporting
PMID: 20020534: ITGB3 cDNA carrying the c.836A>T 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 and αIIbβ3 was shown to be reduced (estimated to be ~20% and ~7% expression compared to wild type, respectively) and the number of cells positive for β3 was also reduced, but higher than most other variants tested (estimated to be ~40% 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.

Not Met criteria codes
PP4
This variant was reported in heterozygosity in one individual (CabGT-24, PMID: 20020534), however sufficient phenotypic information (bleeding phenotype, platelet aggregation) to meet PP4 were not provided.
PM3
This variant has been observed in heterozygosity in one individual (CabGT-24 in PMID: 20020534) in combination with a second ITGB3 variant provisionally classified as a VUS by the VCEP (c.740G>A, p.Gly247Asp), phase unconfirmed.
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.