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]
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Variant: NM_000212.3(ITGB3):c.263G>A (p.Arg88Gln)

CA8622904

627290 (ClinVar)

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: cc2917a9-775d-4047-a02b-5829510184d9

HGVS expressions

NM_000212.3:c.263G>A
NM_000212.3(ITGB3):c.263G>A (p.Arg88Gln)
NC_000017.11:g.47283451G>A
CM000679.2:g.47283451G>A
NC_000017.10:g.45360817G>A
CM000679.1:g.45360817G>A
NC_000017.9:g.42715816G>A
NG_008332.2:g.34610G>A
ENST00000559488.7:c.263G>A
ENST00000559488.5:c.263G>A
ENST00000560629.1:n.228G>A
ENST00000571680.1:c.263G>A
NM_000212.2:c.263G>A

Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 5
PP4 PM2 PM3 BS3 BS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The NM_000212.3(ITGB3):c.263G>A variant in ITGB3 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 88 (Arg88Gln). One patient with the heterozygous Arg88Gln variant and a platelet function defect in PMID: 31064749; however other information such as bleeding history, platelet aggregometry or glycoprotein expression is not available. PP4 criteria not met. The variant is described as a platelet antigen in the literature, determining the HPA-10 genotype. The computational predictor REVEL gives a score of 0.167, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGB3 function (BP4). No splicing impact is expected (SpliceAI predicts a donor gain at at -14bp with a delta score of 0.04) (BP4). Due to insufficient evidence, this variant is classified as a variant of unknown significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: (list criteria applied) BP4. ( VCEP specifications version 2; date of approval: 05/17/2022)
Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.167, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGB3 function (BP4). No splicing impact is expected (SpliceAI predicts a donor gain at at -14bp with a delta score of 0.04).
Not Met criteria codes
PP4
One patient with the Arg88Gln variant and a platelet function defect in PMID: 31064749; however other information such as bleeding history, platelet aggregometry or glycoprotein expression is not available. PP4 criteria not met. The variant is described as a platelet antigen in the literature.
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001504 (3/19,952 alleles) in the East Asian population. There are an additional 0/2818 East Asian alleles in gnomAD v3.1.2 (non-V2) for a total of 3/22,770. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting.
PM3
TGP0247 is reported as heterozygous for Arg88Gln but a second variant is not reported.
BS3
Surface expression of αIIbβ3 measured by flow cytometry/Western blot in COS7 cells transiently co-transfected with Arg88Gln variant β3 and wild type αIIb showed expression at the same level as WT (PMID: 9116286). However, the functionality of the receptor was not assessed.
Surface expression of αIIbβ3 measured by flow cytometry/Western blot in COS7 cells transiently co-transfected with Arg88Gln variant β3 and wild type αIIb showed expression at the same level as WT. PubMed:9116286
BS1
The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001504 (3/19,952 alleles) in the East Asian population. There are an additional 0/2818 East Asian alleles in gnomAD v3.1.2 (non-V2) for a total of 3/22,770 alleles (frequency of 0.0001318). This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting.
Approved on: 2022-06-13
Published on: 2022-06-13
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