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]

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

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CA123254

13568 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

Uncertain Significance

PM2_Supporting PP3 PS3_Supporting

PP4 PM3

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 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.

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.

COS-7 cells transiently transfected with ITGB3 cDNA containing the c.836A>T 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 αIIb and αIIbβ3 (estimated to be ~20% and ~7% expression compared to wild type, respectively), while β3 expression was reduced, but higher than most other variants tested (estimated to be ~40% compared to wild type). PubMed:20020534

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

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