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]

Link to SEPIO compliant JSON-LD document

CA400020401

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ce434843-9a10-4a26-81f6-dff8e7404074

HGVS expressions

NM_000212.2:c.175C>G

NM_000212.3:c.175C>G

ENST00000559488.5:c.175C>G

ENST00000560629.1:n.140C>G

ENST00000571680.1:c.175C>G

NC_000017.11:g.47283363C>G

CM000679.2:g.47283363C>G

NC_000017.10:g.45360729C>G

CM000679.1:g.45360729C>G

NC_000017.9:g.42715728C>G

NG_008332.2:g.34522C>G

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

PM2_Supporting BS3 BP4

PM5

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.175C>G (p.Leu59Val) missense variant has been reported in the literature as an alloantigenic site (PMID: 16686847). However, it has not been reported in association with Glanzmann thrombasthenia. It is at low frequency overall in gnomAD of 0.000006977 and MAF of 0.00001549 (1/64,572 alleles) in the non-Finnish European population. Functional studies in CHO cells have shown no deleterious effect on surface expression or fibrinogen binding (PMID: 16686847 and follow-up studies). In summary, this variant meets criteria to be classified as Likely Benign for GT. GT-specific criteria applied: BS3, BP4, PM2_supporting.

PM2_Supporting

This variant is at an extremely low frequency (below the <1/10,000 threshold) with an overall allele frequency from gnomAD of 0.000006977 and MAF of 0.00001549 (1/64,572 alleles) in the non-Finnish European population.

BS3

CHO-K1 cells were established expressing either the WT Leu59 or Val59 variant ITGB3 with the WT ITGA2B. Surface expression, examined by flow cytometry, found that MoAbs 19‐7 and 23‐15 bound the β3‐Leu33 and β3‐Val33 forms (PMID: 16686847) and binding to soluble fibrinogen was normal at 500ng fibrinogen, although binding was lower at reduced concentrations (data from follow up paper doi 10.1159/000092578; no PMID).

BP4

There is consensus among SIFT, Polyphen, and MutationTaster that this variant does not have a damaging effect. The REVEL score is 0.172, below the <0.25 threshold.

PM5

Leu59Pro has been reported at this same amino acid residue, however it is has been classified as Benign by the ClinGen Platelet Disorders VCEP.

Approved on: 2020-06-16

Published on: 2021-01-28

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