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.506G>A (p.Arg169Gln)

CA123232

13557 (ClinVar)

Gene: ITGB3
Condition: Glanzmann's thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
UUID: 446275dc-0238-4035-8952-0d379747c458
Approved on: 2019-08-07
Published on: 2021-01-28

HGVS expressions

NM_000212.2:c.506G>A
NM_000212.2(ITGB3):c.506G>A (p.Arg169Gln)
NC_000017.11:g.47284587G>A
CM000679.2:g.47284587G>A
NC_000017.10:g.45361953G>A
CM000679.1:g.45361953G>A
NC_000017.9:g.42716952G>A
NG_008332.2:g.35746G>A
NM_000212.3:c.506G>A
ENST00000559488.5:c.506G>A
ENST00000560629.1:n.471G>A
ENST00000571680.1:c.506G>A
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Benign

Met criteria codes 2
BA1 BS3
Not Met criteria codes 3
PM5 BS2 BP4

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The c.506G>A (p.Arg169Gln) missense variant has been reported in the literature many times as the Penb antigenic epitope. However, this polymorphism has not been reported in association with Glanzmann thrombasthenia. It is present in a Latino control population at an allele frequency of 0.01439 and functional studies in CHO cells have shown no deleterious effect on surface expression or fibrinogen binding. In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BS3.
Met criteria codes
BA1
The overall allele frequency in gnomAD is 0.002135; and the highest population allele frequency is 0.01439 (Latino with 510/35,438 alleles). This is above the frequency cutoff of 0.24%.
BS3
Stable CHO cell lines were established expressing either the WT Arg143 or Gln143 ITGB3 with the WT ITGA2B. Surface expression examined by flow cytometry revealed normal expression. Normal adhesive properties were found by measurement of the binding of the LIBS antibody. Normal binding was also observed for both soluble and immobilized fibrinogen. Outside-in signaling was found to be unaffected based on normal tyrosine phosphorylation of pp125FAK.

Not Met criteria codes
PM5
A nonsense variant, Arg169Ter, has been observed at this same amino acid residue but no additional missense variants have been reported to our knowledge.
BS2
One homozygous individual has been evaluated for platelet aggregation and did not have significant disruption of platelet aggregation using ADP, arachidonic acid, thrombin, epinephrine, collagen, and ristocetin. However, this is the only reported homozygote who has been tested so the threshold of >1 individual has not been met.

BP4
There are conflicting predictions of pathogenicity; SIFT predicts it to be tolerated PolyPHen2 possibly damaging and MutationTaster predicts it to be disease causing. The REVEL score of 0.255 is above the threshold of <0.25.
Curation History
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