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 computed assertion could be determined for this classification!

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

CA123254

13568 (ClinVar)

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 5a767207-8239-464f-a198-590b669dbabb
Approved on: 2024-10-15
Published on: 2024-10-16

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
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Uncertain Significance

Met criteria codes 3
PS3_Supporting PP3 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

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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.836A>T replaces the lysine residue with a methionine residue (p.Lys279Met). The highest population minor allele frequency in gnomAD v4.1 is 0.00004005 (3/74904 alleles) in the African/African-American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The variant is predicted by in silico tools to be damaging to protein function (REVEL 0.744; PP3). 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; PS3_supporting). 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
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
PP3
The REVEL score for this variant is 0.744, exceeding the VCEP-established threshold of ≥ 0.7 to apply PP3.
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.1 is 0.00004005 (3/74904 alleles) in the African/African-American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).
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
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