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

CA400020703

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2cef8483-3cc2-4e90-85ea-3f6d6c80e195

HGVS expressions

NM_000212.3:c.262C>T

NM_000212.2:c.262C>T

ENST00000559488.5:c.262C>T

ENST00000560629.1:n.227C>T

ENST00000571680.1:c.262C>T

NC_000017.11:g.47283450C>T

CM000679.2:g.47283450C>T

NC_000017.10:g.45360816C>T

CM000679.1:g.45360816C>T

NC_000017.9:g.42715815C>T

NG_008332.2:g.34609C>T

Pathogenic

PM3_Supporting PP4_Strong PM2_Supporting PVS1

PP1

Evidence Links 2

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.3(ITGB3):c.262C>T variant predicts a nonsense change, Arg88Ter, in exon 3/15, which results in a severely truncated transcript that is expected to undergo NMD. It is reported at a very low frequency (<0.0001) in the non-Finnish European population in gnomAD v2.1.1 and v3. At least 2 compound heterozygous GT patients have been reported in the literature. In summary, the variant meets criteria to be classified as pathogenic. GT-specific criteria met: PVS1, PP4_Strong, PM2_Supporting, PM3_Supporting.

PM3_Supporting

PM3_Supporting is applied for 1 compound heterozygous proband from PMID: 25728920. Variant not confirmed in trans, Leu705CysfsTer4, is classified as pathogenic by the Platelet Disorders VCEP.

PP4_Strong

Proband from PMID: 25728920 meets criteria for PP4_Strong including bleeding phenotype, abnormal platelet aggregation in response to >2 agonists and normal aggregation to ristocetin, reduced αIIbβ3 integrin expression on flow cytometry and full sequencing of ITGA2B and ITGB3 both genes.

PubMed:25728920

PubMed:16463284

PM2_Supporting

The Arg88Ter variant is reported at a frequency of 0.00001549 (1/64572 NFE alleles) in gnomAD v3 and at the highest MAF of 0.0001385 (1/7222) in the "Other" population. However, the MAF in NFE is 0.000007745 (1/129114 alleles). PM2_Supporting is applied based on frequency in the non-Finnish European population.

PVS1

The Arg88Ter introduces a premature termination codon in exon 3/15. NMD is predicted.

PP1

GT33a and GT33b from PMID: 25728920 are siblings, both affected and compound heterozygous for this variant and Leu705CysfsTer4. However, PP1 cannot be applied as phase is not confirmed.

Approved on: 2020-09-08

Published on: 2021-01-22

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